Clinical trial NCT02564978
Conditions: Age-Related Macular Degeneration
Keywords: Eye Disease Degenerative
Sponsor: National Eye Institute (NEI)
Start date: 2016-12-14; Completion date: 2023-03-08
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Age-related macular degeneration (AMD) is the main reason older people lose their vision. It affects the macula, the center of the retina needed for sharp, clear vision. Researchers want to see if an antibiotic can help people with an advanced form of AMD, Geographic Atrophy (GA).

Objective:

To see if minocycline is safe for people with GA and if it helps preserve their vision.

Eligibility:

People age 55 and older who have GA in at least one eye.

Design:

Participants will be screened with physical exam, medical history, blood tests, and eye exam.

Participants will take minocycline. They will take 1 pill twice a day for at least 3 years.

Participants will have a minimum of 11 study visits. (But they are not every 3 months.). At each visit, participants will have a medical history. They may have:

Blood tests.

Eye exam. Vision, eye pressure, and eye movements will be checked. The pupils may be dilated. The inside of the eyes may be photographed.

Their thyroid gland felt while they swallow.

Microperimetry. They will sit in front of a computer and press a button when they see a light on the screen.

Fluorescein angiography. An intravenous line (IV) will be placed in an arm vein. A dye called fluorescein will be placed in the IV and travel through the veins to the blood vessels in the eyes. A camera will take pictures of the dye as it flows through the eye blood vessels.

Detailed description:
Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people over age 65 in the United States, is a heterogeneous clinical entity in which retinal degeneration occurs predominantly in the macula in the context of aging and leads to impairment of central visual acuity (VA). AMD occurs in two general forms, one of which involves choroidal neovascularization (CNV) with subsequent formation of a disciform scar. This is often referred to as the neovascular or wet form. A second form, the subject of this study, is termed dry /atrophic macular degeneration or otherwise geographic atrophy (GA) and involves a slow progressive atrophy of retinal pigment epithelial (RPE) cells and photoreceptors in the macula, also resulting in central vision loss. GA is estimated to affect up to one million persons in the U.S. and there is no current treatment that can prevent its onset or retard its progression.

While the etiology of GA is not completely understood, inflammatory processes involving the activation of resident immune cells of the retina called microglia is likely to contribute. Minocycline inhibits the activation of microglia which produce inflammatory factors implicated in GA development. The objective of this study is to investigate the safety and possible efficacy of oral minocycline in patients with GA.

Study Population: Forty-five participants with unilateral or bilateral GA associated with AMD will be enrolled. However, up to an additional 15 participants may be enrolled to replace participants who may withdraw from the study prior to reaching the Month 33 visit.

Design: This is a multi-center, prospective, single-arm, Phase II study to evaluate minocycline as a potential treatment to decrease the rate of worsening of GA associated with AMD.

Participants will undergo a nine-month run-in phase prior to receiving investigational product (IP). During this run-in phase, participants will have a total of four pre-treatment visits. Following the run-in phase, beginning at Month 9, participants will receive an oral dose of 100 mg of minocycline twice daily for 36 months. There will be a common termination date, which will take place when the last recruited participant has received 36 months of treatment. Participants who were recruited in the earlier part of the study will continue treatment and be followed every six months until the common termination date. However, participants may complete participation in the study as early as Month 45, at the discretion of the investigator.

Outcome Measures: The primary outcome is the rate of change in area of GA based on grading by an external Reading Center of fundus autofluorescence (FAF) images in the assigned study eye. The primary outcome will compare the rates of GA area expansion as determined on FAF images before and following the initiation of IP until 24 months of treatment. Secondary outcomes will compare differences in rates of change in best-corrected visual acuity (BCVA), low-luminance VA, area of GA based on FAF (using a different statistical approach compared to primary outcome) and fundus photography. The exploratory outcome will compare the difference in the rate of change in macular sensitivity as measured using microperimetry. This outcome was originally a secondary outcome when the clinical trial participants were enrolled, since these represent visual function data corresponding closely to areas affected by geographic atrophy. Hence, changes in microperimetry data over time might be well placed to support changes in structural data over time, as geographic atrophy lesions undergo enlargement. In the original Statistical Analysis Plan, the intention was that "Macular sensitivity, as measured on microperimetry, will be evaluated in a similar manner as BCVA", (i.e., Mean rate of change in BCVA during the treatment phase will be compared to the mean rate of change in BCVA during the run-in phase using Student s paired t-test ). However, microperimetry data (represented by multiple numerical values, one for each anatomical location, at each time-point) are much more complex than BCVA data (represented by a single numerical value at each time-point). The originally proposed statistical treatment is therefore not suitable. In addition, the study team is not aware of any established methods accepted by the community for analyzing microperimetry data, unlike the situation for BCVA. Indeed, the microperimetry acquisition pattern used in GA MIN is unique and was developed specifically for this trial. It therefore needs its own dedicated set of statistical analyses (which may need several iterations), rather than pre-specified and widely accepted analyses that could be detailed in advance in the Statistical Analysis Plan. For these reasons, although the original intention was for the microperimetry data to represent a secondary outcome measure, it is better suited to an exploratory outcome measure. Safety outcomes will include the number and severity of adverse events (AEs). Ocular safety outcomes will be indicated by changes in VA, ocular surface changes, intraocular inflammation and any other ocular changes not consistent with the natural progression of GA.

Arms: arm 1: Oral administration of minocycline.
Interventions: intervention 1: Minocycline
Intervention descriptions: intervention 1: Adult participants will be instructed to take their prescribed IP orally two times a day, once in the morning and once in the evening, approximately 12 hours apart. The capsules will be dispensed to the participant in a tight, light-resistant container as defined in the USP in three-month supply aliquots. Starting at Month 9 and continuing at Month 12, a three-month supply will be dispensed to the participant during the study visit or mailed to the participant. Participants will be given an instruction sheet for taking the prescribed IP. Starting at Month 15 participants will receive two bottles for a six-month supply. The IP should be stored between 15-30 degrees C (or 59-86 degrees F).They should be protected from light, moisture, and excessive heat. Participants will be required to bring their bottles of IP to each appropriate visit for capsule counts for compliance monitoring.

Protocol documents:
ICF_002.pdf: 























Prot_000.pdf: 


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Project Uses Ionizing Radiation:
 No 
 Yes
IND/IDE:
 No
 Yes
Drug/Device/#: 108,154
Sponsor: 
EUDRACT:
 No
 Yes
Drug/Device/#: 2017-000946-24
Sponsor: National Eye Institute
Durable Power of Attorney:
 No
 Yes
Multi-institutional Project:
 No
 Yes
Site
FWA
Coordinating Center: National Eye Institute (NEI)
FWA00005897
Participating Center: Bristol Eye Hospital (BEH)
Principal Investigator: 
FWA00000523
Additional sites may be identified and added to this study in future amendments.
Data and Safety Monitoring Board: 
 No
 Yes
Technology Transfer Agreement: 
 No
 Yes
Confidential Disclosure Agreement:
 No
 Yes
Samples Being Stored for Future Research: 
 No
 Yes
Flesch-Kincaid Reading Level of Consent Form:
8.9


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TABLE OF CONTENTS
PROTOCOL ABBREVIATIONS LIST.................................................................................................VI
PRÉCIS .............................................................................................................................................1
1.0
INTRODUCTION.......................................................................................................................3
1.1
Age-related Macular Degeneration...................................................................................3
1.2
Treatment of Age-related Macular Degeneration.............................................................3
1.3
Geographic Atrophy .........................................................................................................4
2.0
SCIENTIFIC RATIONALE FOR USE OF ORAL MINOCYCLINE IN THE TREATMENT OF GA ...5
2.1
Microglial Involvement in the Inflammatory Etiology of AMD......................................5
2.2
Minocycline as an Inhibitor of Microglial Activation: Preclinical Studies......................5
2.3
Minocycline: Clinical Use and Clinical Studies...............................................................6
3.0
STUDY OBJECTIVE .................................................................................................................7
4.0
PARTICIPANTS........................................................................................................................7
4.1
Participant Eligibility Criteria...........................................................................................7
4.1.1
Inclusion Criteria ...............................................................................................7
4.1.2
Exclusion Criteria ..............................................................................................8
4.2
Study Eye Eligibility Criteria ...........................................................................................9
4.2.1
Study Eye Inclusion Criteria..............................................................................9
4.2.2
Study Eye Exclusion Criteria...........................................................................10
4.2.3
Choice of Study Eye in Cases of Bilateral Disease .........................................10
5.0
STUDY DESIGN AND METHODS ............................................................................................11
5.1
Study Overview ..............................................................................................................11
5.2
Recruitment.....................................................................................................................11
5.3
Screening ........................................................................................................................12
5.4
Study Design...................................................................................................................13
5.5
Study Procedures ............................................................................................................13
5.6
Ocular and Systemic Evaluations ...................................................................................14
5.7
Study and Concomitant Therapies..................................................................................16
5.7.1
Formulation of Minocycline at NEI ................................................................16
5.7.2
Formulation of Minocycline at BEH ...............................................................16
5.8
Dosage, Administration and Storage ..............................................................................16
5.9
Concomitant Therapy .....................................................................................................17
5.10 Investigational Product Accountability ..........................................................................17
5.11 Follow-up/Termination Procedures................................................................................17
5.12 Storage of Samples and Data..........................................................................................18


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TABLE OF CONTENTS (CONTINUED)
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6.0
RISKS/DISCOMFORTS...........................................................................................................18
6.1
Examination Risks..........................................................................................................18
6.1.1
Risks Associated with Minocycline.................................................................19
6.1.2
Drug Interaction-related...................................................................................21
7.0
PARTICIPANT SAFETY MONITORING...................................................................................21
7.1
Participant Withdrawal Criteria......................................................................................22
7.2
Pregnancy Monitoring ....................................................................................................22
8.0
OUTCOME MEASURES..........................................................................................................23
8.1
Primary Outcome............................................................................................................23
8.2
Secondary Outcomes ......................................................................................................23
8.3
Exploratory Outcome......................................................................................................23
8.4
Ocular Safety Outcomes.................................................................................................24
9.0
STATISTICAL ANALYSIS .......................................................................................................24
9.1
Study Design and Primary Analysis...............................................................................24
9.2
Handling Data Irregularities ...........................................................................................25
9.3
Analysis of Secondary Endpoints...................................................................................26
9.4
Sample Size/Accrual Rate ..............................................................................................27
10.0 HUMAN PARTICIPANTS PROTECTION..................................................................................28
10.1 Equitability .....................................................................................................................28
10.1.1
Justification for Exclusion of Children............................................................29
10.1.2
Justification for Exclusion of Pregnant or Lactating Women .........................29
10.1.3
Refraction and Visual Acuity ..........................................................................29
10.1.4
Photography Qualification...............................................................................29
10.1.5
Professional Licensure.....................................................................................30
11.0 ANTICIPATED BENEFIT ........................................................................................................30
12.0 CONSENT DOCUMENTS AND PROCESS.................................................................................30
13.0 DATA AND SAFETY MONITORING........................................................................................30
13.1 Coordinating Center........................................................................................................31
13.2 Data and Safety Monitoring Committee.........................................................................31
13.3 Criteria for Stopping the Study.......................................................................................32


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14.0 QUALITY ASSURANCE ..........................................................................................................32
15.0 REPORTABLE EVENTS..........................................................................................................33
16.0 ALTERNATIVES TO PARTICIPATION ....................................................................................33
17.0 PRIVACY ...............................................................................................................................33
18.0 CONFIDENTIALITY ...............................................................................................................33
19.0 CONFLICT OF INTEREST.......................................................................................................33
20.0 TECHNOLOGY TRANSFER ....................................................................................................33
21.0 RESEARCH AND TRAVEL COMPENSATION ..........................................................................34
22.0 REFERENCES ........................................................................................................................35
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL...........................................................40
APPENDIX 2: STUDY FLOWSHEET.................................................................................................41
APPENDIX 3: GEOGRAPHIC ATROPHY GRADING PROCEDURES FROM DIGITIZED 
PHOTOGRAPHS....................................................................................................................44
APPENDIX 4: PARTICIPANT REMINDERS ......................................................................................45


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PROTOCOL ABBREVIATIONS LIST
AE
Adverse Event
ALS
Amyotrophic Lateral Sclerosis
AMD
Age-Related Macular Degeneration
AREDS
Age-Related Eye Disease Study
BCVA
Best-Corrected Visual Acuity
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CC
Clinical Center
CD
Clinical Director
CFH
Complement Factor H
CNS
Central Nervous System
CNV
Choroidal Neovascularization
CRIS
Clinical Research Information System
CTCAE
Common Terminology Criteria for Adverse Events
DIRRL
Doheny Image Reading & Research Lab
DSMC
Data and Safety Monitoring Committee
EDC
Electronic Data Capture
Emmes
The Emmes Company, LLC
EMR
Electronic Medical Record
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT
European Clinical Trials Database
EVA
Electronic Visual Acuity
FA
Fluorescein Angiography
FAF
Fundus Autofluorescence
FDA
Food and Drug Administration
FSH
Follicle-Stimulating Hormone
GA
Geographic Atrophy
ICRRC
Intramural Clinical Research Review Committee
IND
Investigational New Drug
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board


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PROTOCOL ABBREVIATIONS LIST (CONTINUED)
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MI
Multiple Imputation
MPS DA
Macular Photocoagulation Study Disk Area
NEI
National Eye Institute
NGF
Nerve Growth Factor
NIH
National Institutes of Health
OCT
Optical Coherence Tomography
OD
Oculus Dexter (Right Eye)
OS
Oculus Sinister (Left Eye)
PI
Principal Investigator
RPE
Retinal Pigment Epithelial 
SAE
Serious Adverse Event
SNP
Single Nucleotide Polymorphism
SPF
Sun Protection Factor
TFT
Thyroid Function Test
USP
United States Pharmacopeia
UV
Ultraviolet
VA
Visual Acuity
VEGF
Vascular Endothelial Growth Factor
YAG
Yttrium Aluminum Garnet


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PRÉCIS
Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people 
over age 65 in the United States, is a heterogeneous clinical entity in which retinal degeneration 
occurs predominantly in the macula in the context of aging and leads to impairment of central 
visual acuity (VA). AMD occurs in two general forms, one of which involves choroidal 
neovascularization (CNV) with subsequent formation of a disciform scar. This is often referred to 
as the neovascular or “wet” form. A second form, the subject of this study, is termed “dry” 
/atrophic macular degeneration or otherwise “geographic atrophy” (GA) and involves a slow 
progressive atrophy of retinal pigment epithelial (RPE) cells and photoreceptors in the macula, 
also resulting in central vision loss. GA is estimated to affect up to one million persons in the U.S. 
and there is no current treatment that can prevent its onset or retard its progression. 
While the etiology of GA is not completely understood, inflammatory processes involving the 
activation of resident immune cells of the retina called microglia is likely to contribute. 
Minocycline inhibits the activation of microglia which produce inflammatory factors implicated 
in GA development. The objective of this study is to investigate the safety and possible efficacy 
of oral minocycline in patients with GA.
Study Population: Forty-five participants with unilateral or bilateral GA associated with AMD 
will be enrolled. However, up to an additional 15 participants may be enrolled to replace 
participants who may withdraw from the study prior to reaching the Month 33 visit.
Design: This is a multi-center, prospective, single-arm, Phase II study to evaluate minocycline as 
a potential treatment to decrease the rate of worsening of GA associated with AMD. 
Participants will undergo a nine-month run-in phase prior to receiving investigational product (IP). 
During this run-in phase, participants will have a total of four pre-treatment visits. Following the 
run-in phase, beginning at Month 9, participants will receive an oral dose of 100 mg of minocycline 
twice daily for 36 months (i.e., through Month 45). There will be a common termination date, 
which will take place when the last recruited participant has received 36 months of treatment. 
Participants who were recruited in the earlier part of the study will continue treatment and be 
followed every six months until the common termination date. However, participants may 
complete participation in the study as early as Month 45, at the discretion of the investigator. 


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Outcome Measures: The primary outcome is the rate of change in area of GA based on grading 
by an external Reading Center of fundus autofluorescence (FAF) images in the assigned study eye. 
The primary outcome will compare the rates of GA area expansion as determined on FAF images 
before and following the initiation of IP until 24 months of treatment. Secondary outcomes will 
compare differences in rates of change in best-corrected visual acuity (BCVA), low-luminance 
VA, area of GA based on FAF (using a different statistical approach compared to primary 
outcome) and fundus photography. The exploratory outcome will compare the difference in the 
rate of change in macular sensitivity as measured using microperimetry. This outcome was 
originally a secondary outcome when the clinical trial participants were enrolled, since these 
represent visual function data corresponding closely to areas affected by geographic atrophy. 
Hence, changes in microperimetry data over time might be well placed to support changes in 
structural data over time, as geographic atrophy lesions undergo enlargement. In the original 
Statistical Analysis Plan, the intention was that “Macular sensitivity, as measured on 
microperimetry, will be evaluated in a similar manner as BCVA”, (i.e., “Mean rate of change in 
BCVA during the treatment phase will be compared to the mean rate of change in BCVA during 
the run-in phase using Student’s paired t-test”). However, microperimetry data (represented by 
multiple numerical values, one for each anatomical location, at each time-point) are much more 
complex than BCVA data (represented by a single numerical value at each time-point). 
The originally proposed statistical treatment is therefore not suitable. In addition, the study team 
is not aware of any established methods accepted by the community for analyzing microperimetry 
data, unlike the situation for BCVA. Indeed, the microperimetry acquisition pattern used in 
GA MIN is unique and was developed specifically for this trial. It therefore needs its own dedicated 
set of statistical analyses (which may need several iterations), rather than pre-specified and widely 
accepted analyses that could be detailed in advance in the Statistical Analysis Plan. For these 
reasons, although the original intention was for the microperimetry data to represent a secondary 
outcome measure, it is better suited to an exploratory outcome measure. Safety outcomes will 
include the number and severity of adverse events (AEs). Ocular safety outcomes will be indicated 
by changes in VA, ocular surface changes, intraocular inflammation and any other ocular changes 
not consistent with the natural progression of GA.


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1.0
INTRODUCTION
1.1
Age-related Macular Degeneration
AMD is the leading cause of late onset visual impairment and legal blindness in people 65 years 
of age or older in the United States (1, 2). The World Health Organization has placed AMD as the 
third leading cause of blindness worldwide. The phrase “age-related” is associated with macular 
degeneration because data show that the risk of developing AMD dramatically increases after age 
60. It is estimated that 13 million people in the U.S., age 40 and older, have signs and symptoms 
of macular degeneration. Based on population demographics and current prevalence data, the 
number of individuals affected with AMD will double in the year 2020.
AMD is a disease of the macula, the central area within the posterior retina that helps produce 
sharp, central vision. Central vision is required for seeing objects clearly and for common daily 
activities essential for independent living such as reading, writing, sewing and driving. While the 
pathogenesis of AMD remains unknown, several lines of evidence have indicated the role of 
inflammation. Complement factor H (CFH) is a major regulatory factor in the complement 
cascade. Several groups have identified single nucleotide polymorphisms (SNPs) in the CFH gene 
that are associated with AMD. A single copy of the risk-associated haplotype increases the risk of 
AMD by two- to four-fold, whereas those with a dual copy may increase their lifetime risk by 
five- to seven-fold (3-7). Macrophages are known to have an important role in the initiation and 
maintenance of the immune response, including the regulation of complement activation. 
Previous studies have shown that patients with AMD were more likely to have circulating, 
activated macrophages (which produce high amounts of proinflammatory cytokines) compared to 
controls without AMD (8).
1.2
Treatment of Age-related Macular Degeneration
Treatment of AMD has mostly focused on therapy for neovascular AMD. These have included 
classic laser photocoagulation, photodynamic therapy (verteporfin, Visudyne) and anti-vascular 
endothelial growth factor (VEGF) pegylated aptamer (pegaptanib sodium, Macugen), an 
anti-VEGF monoclonal antibodies ranibizumab (Lucentis) and aflibercept.


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In October 2001, the results of the Age-Related Eye Disease Study (AREDS), a multi-center, 
randomized, controlled clinical trial of high-dose vitamins C and E, beta carotene and zinc 
supplements demonstrated a 25% reduction in the risk of progression to late AMD (9). 
However, this effect appears to be limited to reducing risk for progressing to neovascular AMD 
and does not influence the risk for progression to GA (unpublished data).
There are currently no available treatments or therapies for GA that have demonstrated efficacy in 
either preventing the onset, slowing the progression of disease, or improving vision of affected 
patients.
1.3
Geographic Atrophy
Atrophic AMD or GA is characterized by an absence of neovascular changes and the gradual 
progression of atrophic changes in the macula on the level of outer retina and the RPE cell layer, 
resulting in progressive central vision loss. Over time, this progresses to result in serious 
impairment of central vision and often legal blindness. Wet or exudative AMD can also arise in 
the context of GA. Both GA involving the center of the macula and wet AMD are considered forms 
of late AMD.
One of the most common signs in early or intermediate AMD is drusen, which is typically seen in 
people over the age of 60. Drusen are usually seen clinically as whitish-yellow irregularities under 
the retina. Large drusen have been shown to contain immunoglobulins, activated microglia and 
fragments of activated complement factors (10-12), which may be a source of chronic 
inflammatory stimulus in the aging retina. In the absence of findings consistent with late AMD, 
intermediate AMD is typically defined as the presence of large (>125µm) macular drusen and/or 
pigmentary (hypopigmentary or hyperpigmentary) changes, while early AMD is typically defined 
as the presence of macular drusen < 125µm in size.


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2.0
SCIENTIFIC RATIONALE FOR USE OF ORAL MINOCYCLINE IN THE TREATMENT OF GA
2.1
Microglial Involvement in the Inflammatory Etiology of AMD
While the etiology of AMD is not completely understood, chronic neuroinflammation in the retina 
is thought to play an important causative role (13). Genetic analyses have implicated immune 
molecules, particularly those in the complement system, in conferring risk for AMD (14-16). 
Drusen, the hallmark of early and intermediate AMD, contain complement molecules (11, 17), as 
well as oxidation products from lipid and carbohydrates that can initiate inflammatory and immune 
responses (18, 19).
Microglia are the primary resident immune cells in the retina and are implicated in the response 
and 
propagation 
of 
relevant 
pathological 
inflammatory 
processes 
in 
AMD 
(13). 
Activated microglia and macrophages have been found in the outer retina of AMD eyes (20, 21) 
and in close proximity to GA lesions (22). In mouse models of AMD, outer retinal accumulations 
of activated microglia are prominent and associated with late AMD lesions. Activated microglia 
in the outer retina appear capable of inducing cellular changes in the outer retina that characterize 
GA, such as the loss in RPE integrity and regularity (23), as well as photoreceptor cell death (24). 
Inhibition of microglia/macrophage recruitment to the outer retina in mouse models decreases 
photoreceptor degeneration in AMD-related animal models, further implicating their causal role 
(25). As a result, inhibition of microglial activation may be a promising therapeutic approach in 
AMD (26) in limiting the production of pro-inflammatory mediators in the outer retina and 
arresting/retarding progressive RPE and photoreceptor degeneration in GA.
2.2
Minocycline as an Inhibitor of Microglial Activation: Preclinical Studies
Minocycline is a member of the tetracycline family of antibiotics that in addition to its 
antimicrobial properties acts as an anti-inflammatory agent and an inhibitor of microglial 
activation (27, 28). Minocycline can exert its anti-inflammatory effects on microglia in culture, 
inhibiting proliferation and release of proinflammatory mediators (IL-1β, IL-6, TNF-α, NO), and 
promoting production of nerve growth factor (NGF), leading to decreased inflammatory cell death 
and increased neuroprotection (29-31). Minocycline crosses the blood-Central Nervous System 
(CNS) barrier readily, providing high bioavailability in the CNS; as a result, it has been evaluated 


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as a therapy in a number of animal disease models where microglial-mediated neuroinflammation 
features. In a mouse model of diabetic retinopathy, systemic minocycline decreased inflammatory 
cytokine production, reduced the release of cytotoxins from activated microglia, and lowered 
the rate of apoptosis in the retina (32). In a mouse model of subretinal hemorrhage, 
intraperitoneally-administered minocycline reduced microglial infiltration into the outer retina and 
delayed consequent photoreceptor atrophy (33). In mouse models of retinal degeneration in which 
pro-inflammatory cytokine production and microglial activation occur (34-38), systemic 
minocycline was found effective in slowing down the rate of photoreceptor cell death (39, 40).
2.3
Minocycline: Clinical Use and Clinical Studies
Minocycline is FDA-approved for treating infectious disorders and is indicated for the treatment 
of various gram-positive and -negative bacteria. In ophthalmology, oral minocycline is commonly 
used for the treatment of blepharitis and ocular rosacea (41). It has a favorable side-effect profile, 
although it should not be used in pregnancy as the use of tetracycline class of drugs during tooth 
development may cause permanent tooth discoloration.
Oral minocycline is used widely and has been shown to be well tolerated when used at the 
FDA-approved doses. A study comparing the AEs reported with the number of prescriptions for 
minocycline for the years 1998 to 2003 estimated the rate to be 13 reported AEs per million 
prescriptions per year (42). The majority of these events were gastrointestinal upset, 
photosensitivity, hyperpigmentation, and tooth discoloration.
Minocycline has also been used in clinical trials as an inhibitor of microglial activation. In a 
clinical trial of acute stroke, 74 patients treated with oral minocycline (200 mg) for five days 
demonstrated a significantly better neurological outcome compared with 77 patients on placebo 
(43). Minocycline is currently being investigated in ongoing clinical studies to decrease symptom 
progression in Huntington’s disease (NCT00277355), and to provide neuroprotection in 
Parkinson’s disease (NCT00063193) and amyotrophic lateral sclerosis (ALS) (NCT00047723). 
In the area of retinal diseases, a pilot, proof-of-concept study of diabetic macular edema reported 
an association between oral minocycline administration and improved visual function, retinal 
edema, and vascular leakage (NCT01120899) (44).


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3.0
STUDY OBJECTIVE
The primary objective of this study is to investigate the safety and possible efficacy of oral 
minocycline for slowing down the worsening of GA associated with AMD.
4.0
PARTICIPANTS
Forty-five participants, ages 55 years and older, with unilateral or bilateral GA associated with 
atrophic AMD will be initially accrued. Approximately 20-25 participants will be enrolled at NEI, 
and approximately 20-25 participants will be enrolled at BEH to reach the target sample size of 45 
participants. Participants who withdraw or are lost to follow-up before the termination of 
enrollment at all sites may be replaced by new enrollments up to 30 participants at NEI and 30 
participants at BEH. Listed below are the inclusion and exclusion criteria.
4.1
Participant Eligibility Criteria
4.1.1
Inclusion Criteria
To be eligible, the following inclusion criteria must be met, where applicable:
1. Participant must be 55 years of age or older.
2. Participant must understand and sign the protocol’s informed consent document.
3. Participant must have evidence of early or intermediate AMD as defined by characteristic 
presence of drusen and/or pigmentary changes.
4. Participant must be able to swallow capsules.
5. Participant must have normal renal function and liver function or have mild abnormalities 
not above grade 1 as defined by the Common Terminology Criteria for Adverse Events 
v4.0 (CTCAE).
6. Participant must agree to minimize exposure to sunlight or artificial ultraviolet (UV) rays 
and to wear protective clothing, sunglasses and sunscreen (minimum sun protection factor 
(SPF) 15) if s/he must be out in the sun.


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7. Any female participant of childbearing potential (see Appendix 1 for definition) must have 
a negative pregnancy test at screening and be willing to undergo pregnancy tests throughout 
the study.
8. Any female participant of childbearing potential (see Appendix 1 for definition) and any 
male 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 two acceptable methods of contraception throughout the course of the study and 
for at least one week after investigational product (IP) discontinuation. Acceptable methods 
of contraception include:
a.
hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or 
vaginal ring),
b. intrauterine device,
c.
barrier methods (diaphragm, condom) with spermicide, or,
d. surgical sterilization (hysterectomy or tubal ligation).
*Abstinence is only acceptable when it is the participant’s preferred and usual lifestyle 
choice. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
A participant is not eligible if any of the following exclusion criteria are present.
1. Participant is actively receiving study therapy in another investigational study.
2. Any female participant of childbearing potential (see Appendix 1 for definition) that is 
pregnant, breast-feeding or planning to become pregnant during the study.
3. Participant is expected to be unable to comply with study procedures or follow-up visits.
4. Participant is on ocular or systemic medications known to be toxic to the lens, retina or 
optic nerve (e.g., ethambutol, chloroquine, or hydroxychloroquine).
5. Participant has a condition that would preclude participation in the study (e.g., unstable 
medical status including blood pressure and glycemic control) by interfering with the 
participant’s ability to engage in the required protocol evaluation and testing and/or comply 
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6. Participant has a history of chronic renal failure requiring dialysis or kidney transplant.
7. Participant has a history of chronic hepatitis or liver failure.
8. Participant has a history of thyroid cancer.
9. Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline 
family.
10. Participant is currently taking minocycline or another tetracycline medication.
11. Participant is taking any medication that could adversely interact with minocycline such as 
methoxyflurane.
12. Participant has a prior history of idiopathic intracranial hypertension.
4.2
Study Eye Eligibility Criteria
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below.
4.2.1
Study Eye Inclusion Criteria
1. The study eye must have greater than ½ disc area (approximately 1 mm2) of GA compatible 
with dry AMD. GA is defined as one or more well-defined and often circular patches of 
partial or complete depigmentation of the RPE, typically with exposure of underlying 
choroidal blood vessels. Even if much of the RPE appears to be preserved and large 
choroidal vessels are not visible, a round patch of RPE partial depigmentation may be 
classified as early GA. The GA in the study eye must be able to be photographed in their 
entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can 
complicate area measurements.
2. The total area of GA lesions combined should be less than 7.0 Macular Photocoagulation 
Study (MPS) disc areas (DA) (17.78 mm2) as evident on FAF imaging.
3. The VA of the study eye should be ≥19 Electronic Early Treatment Diabetic Retinopathy 
Study (E-ETDRS) letters (i.e., 20/400 or better).


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4. The study eye must have clarity of ocular media and degree of pupil dilation sufficient to 
permit adequate fundus photographs.
4.2.2
Study Eye Exclusion Criteria
1. Current evidence of choroidal neovascularization (CNV) as determined by the treating 
physician or a history of treatments for CNV.
2. Evidence of retinal atrophy due to causes other than atrophic AMD.
3. Current evidence or history of ocular disorders in the study eye that in the opinion of the 
investigator confounds study outcome measures, including (but not limited to):
a.
non-proliferative diabetic retinopathy involving 10 or more hemorrhages or 
microaneurysms, or active proliferative diabetic retinopathy,
b. Branch or central retinal vein or artery occlusion,
c.
Macular hole,
d. Pathologic myopia,
e.
Uveitis,
f.
Pseudovitelliform maculopathy.
4. History of vitreoretinal surgery.
5. Need for ocular surgery during the course of the study.
6. Recent history of lens removal (< three months) or Yttrium Aluminum Garnet (YAG) laser 
capsulotomy (< one month).
4.2.3
Choice of Study Eye in Cases of Bilateral Disease
If both eyes meet the study eye eligibility criteria described above, the eye with the better BCVA 
will be chosen as the study eye. If both eyes are of equal VA, the study eye will be assigned by the 
enrolling investigator. For participants with two qualifying eyes, the fellow (non-study) eye will 
be noted as a “qualifying fellow eye” and anatomical data from it will be analyzed as part of the 
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5.0
STUDY DESIGN AND METHODS
5.1
Study Overview
This is a multi-center, prospective, single-arm, Phase II clinical trial of up to 45 participants with 
GA associated with AMD. The amended study design relies on the linearity of the GA expansion 
rate in the natural history of the disease in a single eye using the square root transformation of the 
GA area. The linearity of GA expansion rate over the time scales relevant to the study were verified 
in exploratory analyses on two previous GA studies Othera (NEI Protocol 06-EI-0116) and SIRGA 
(NEI Protocol 09-EI-0008).
Participants will undergo a nine-month run-in period prior to receiving IP. Starting at Month 9 
(IP start visit), participants will receive 100 mg minocycline orally twice a day for a total of at 
least 36 months (i.e., through Month 45). All participants will be followed for a minimum of 45 
months over 11 or more study visits. There will be a common termination date, which will take 
place on or after the date when the last-recruited participant has received 36 months of IP, although 
some participants may complete participation in the study as early as Month 45, at the discretion 
of the investigator. As GA is a slow, progressive, retinal disease involving the gradual expansion 
of the area of atrophy on a time-scale of square microns per month, every effort will be made to 
retain participants for the entire duration of the study.
5.2
Recruitment
Forty-five participants will be initially enrolled in this study. However, up to an additional 
15 participants may be enrolled to replace participants who may withdraw prior to reaching the 
Month 33 visit.
Approximately 20-25 participants will be recruited from the NEI clinic, and most of the 
participants for this study can be recruited from the current patient population with GA and AMD 
at the NEI retina clinic. The study will also rely on referrals from physicians at Kaiser Permanente 
and other local eye clinics. A recruitment flyer will be posted at community gathering places 
including but not limited to: hospitals, libraries, senior centers, senior housing facilities, area metro 
and bus stops, websites, newspapers and throughout the NIH campus. Recruitment materials such 
as letters to physicians and potential participants will be used. It is anticipated that all participants 
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Approximately 20-25 participants will be recruited from the BEH site. Participants from this site 
will be identified following attendance at routine outpatient appointments or sent a recruitment 
letter from existing databases of patients diagnosed with GA and AMD and who routinely attend 
the BEH site for treatment.
It is anticipated that all participants will be recruited within 12 months. The recruitment totals are 
not fixed at each site. No more than 30 participants will be enrolled at either the NEI or UK site.
5.3
Screening
Consent will be obtained before any study procedures are done, including any screening 
procedures that may be done under this current protocol. At the NEI clinic, all potential participants 
will undergo a screening visit in the NEI ophthalmology clinic to determine whether they meet the 
eligibility criteria. Potential participants will be screened under protocols such as the NEI 
screening protocol (NIH Protocol 08-EI-0102), AREDS follow-up protocol (NIH Protocol 
08-EI-0043), Biobank protocol (NIH Protocol 12-EI-0042), or DA AMD protocol (NIH Protocol 
11-EI-0147) to establish eligibility. Each potential participant must have an active signed consent 
for one of the above-mentioned protocols on file in order to allow for screening examination. 
The following tests are performed during the screening protocols and may be used for the initial 
study visit for the current protocol if they are performed within the specified time frames:
1. Stereoscopic color fundus photography, FAF and infrared reflectance imaging, 
microperimetry, and OCT performed within 30 days prior to the initial study visit.
2. Physical examination (including thyroid palpation), acute care panel, hepatic panel, 
complete blood count (CBC) and thyroid function test (TFT) performed within 60 days 
prior to the initial study visit.
Evaluations previously performed outside of the windows indicated above may be used to 
determine participant eligibility, and these evaluations will be repeated under this study at the 
initial study visit. At any time during the screening process, the participant may enroll in this 
current protocol by signing the protocol’s consent form and may complete any remaining screening 
and baseline procedures under this protocol, with final determination of eligibility. Women of 
childbearing potential (see Appendix 1 for definition) must have a negative test within 24 hours 


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prior to initiation of investigational product. If BCVA, manifest refraction, low-luminance visual 
acuity, slit lamp examination, and/or intraocular pressure (IOP) were assessed on an earlier date 
under another protocol, these will be repeated as initial study visit examinations on the day of 
enrollment. If a participant is unable to complete microperimetry testing, the microperimetry 
testing may be waived for subsequent study visits and the investigator will specify the reason the 
test could not be completed. All other screening procedures will not be repeated. 
These screening/initial study visit examinations are outlined in Appendix 2. The enrolling 
Investigator will confirm that all eligibility criteria have been met. If determined eligible, the 
participant will sign the informed consent and enroll at his/her initial study visit.
At the BEH site, all potential participants will only be screened under this study protocol. 
5.4
Study Design 
This study will examine the effect of oral minocycline in participants with GA in at least one eye 
that is associated with AMD. Participants will undergo a nine-month run-in period prior to 
receiving IP. During the run-in period, participants will return to the clinic at Months 3, 6 and 9 
for ocular assessments. Starting at Month 9, participants will receive 100 mg minocycline orally 
twice a day from the IP start visit until study termination. Participants will return to the clinic at 
Months 12, 15 and every six months thereafter. The study is designed with a common termination 
date, meaning it will not terminate until the last recruited participant has completed the Month 45 
visit. Therefore, participants enrolled at the beginning of the study could receive additional months 
of IP beyond the scheduled 36 months. However, participants may complete participation in the 
study as early as Month 45, at the discretion of the investigator. Although participants may 
withdraw from IP during the study, all participants will be asked to return for all visits through 
their study termination visit.
5.5
Study Procedures
The study will require a minimum of 11 visits (Months 0, 3, 6, 9, 12, 15, 21, 27, 33, 39 and 45). 
All visits must be conducted within a window of  30 days. It is anticipated that the study duration 
will not exceed 57 months if all participants are recruited within the first 12 months. At or prior to 
the IP start visit, the participant will undergo a complete vital sign assessment and a complete 


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review of systems. Comprehensive ophthalmologic examinations and safety assessments will be 
performed as outlined in the study flowsheet (Appendix 2).
If participants are on anticoagulation at enrollment, they must visit their prescribing physician to 
check their anticoagulation status within two-four weeks after initiating IP to have their 
anticoagulation regimen adjusted if necessary (as taking minocycline may require an increase of 
anticoagulation medication dose).
Participant compliance with study IP administration will be prompted through ongoing 
encouragements and reminders during study visits and scheduled and unscheduled telephone 
contacts. Compliance will be assessed by capsule counts conducted during study visits. 
Overall compliance rate based on previous long-term studies in AMD with twice daily dosing is 
expected to be fairly good (about five out of six participants took >75% of the study IP) (50c). 
Occurrences in which the computed compliance rate between study visits falls below 50% will be 
reported as a protocol deviation.
5.6
Ocular and Systemic Evaluations
Over the course of the study, participants will undergo the following ocular and systemic 
evaluations as outlined in the study flowsheet (see Appendix 2):
1. Medical/Ophthalmic History
2. Concomitant Medications Assessment
3. Vital Signs
4. Physical Examination
5. Adverse Event Assessment
6. Best-corrected visual acuity (BCVA)
7. Manifest Refraction using Electronic Visual Acuity (EVA) tester 
8. Low-luminance visual acuity (VA) testing (study and qualifying fellow eye(s)) 5
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10. Slit Lamp Examination
11. Dilated Fundus Examination
12. Measurement of retinal sensitivity using microperimetry (mesopic for study eye(s) and 
scotopic for qualifying fellow eye(s))
13. Color Fundus Photography
14. Fundus Autofluorescence (FAF) Imaging
15. Infrared Reflectance Imaging
16. Optical Coherence Tomography (OCT)
17. Fluorescein Angiography (FA)4
18. Acute Care Panel1
19. Hepatic Panel1
20. Complete Blood Count (CBC)
21. Thyroid Function Test (TFT)1,2
22. Thyroid Palpation3
23. Pregnancy Test for Females of Childbearing Potential1 (See Appendix 1 for definition)
1 All clinically significant abnormal values or positive tests will be reported to the participant’s 
primary care physician, with the participant’s permission.
2 Clinically significant abnormal TFT results that emerge during the course of the study will 
lead to referral to an endocrinologist.
3 Clinically significant abnormal findings during a thyroid palpation that emerge during the 
course of the study will be followed by a referral to an endocrinologist.
4 Throughout the study, investigators will review retinal images to definitively ascertain the 
absence of CNV. If the absence of CNV cannot be definitively ascertained based on retinal 
images at the Month 9 visit, FA will be performed. If positive for CNV, the participant will 
be discontinued from the study if they have only one eligible study eye but may continue in 
the study if the fellow eye is eligible.
5 Evaluations on non-qualifying fellow eyes may be performed for routine clinical evaluation 
for the continuing care of the participant as determined by the treating investigator.


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It is expected that these tests can be completed in one clinic visit over one day. 
Physical examination performed within 60 days of study enrollment may be admissible for the 
initial study visit evaluation. In the event that the testing was not completed within a day, 
subsequent clinic visits may be scheduled within 10 days of the first visit to complete the scheduled 
evaluation. The frequency of the tests, however, varies depending on the visit. The schedule for 
each test is outlined in the study flowsheet (Appendix 2).
5.7
Study and Concomitant Therapies
5.7.1
Formulation of Minocycline at NEI
At the NEI site, minocycline hydrochloride capsules for oral administration containing the 
equivalent of 100 mg of minocycline will be investigated under Investigational New Drug (IND) 
Number 108,154.
5.7.2
Formulation of Minocycline at BEH 
At the BEH site, minocycline hydrochloride capsules for oral administration containing the 
equivalent of 100 mg of minocycline will be investigated under European Clinical Trials Database. 
5.8
Dosage, Administration and Storage 
Adult participants will be instructed to take their prescribed IP orally two times a day, once in the 
morning and once in the evening, approximately 12 hours apart. The capsules will be dispensed to 
the participant in a tight, light-resistant container as defined in the United States Pharmacopeia 
(USP) in three-month supply aliquots. Starting at Month 9 and continuing at Month 12, a three-
month supply will be dispensed to the participant during the study visit or mailed to the participant. 
Participants will be given an instruction sheet for taking the prescribed IP (Appendix 4). Starting 
at Month 15 participants will receive two bottles for a six-month supply. The IP should be stored 
between 15-30°C (or 59-86°F). They should be protected from light, moisture, and excessive heat. 
Participants will be required to bring their bottles of IP to each appropriate visit for capsule counts 
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5.9
Concomitant Therapy
The use of periocular and intraocular corticosteroids is not permitted in study eyes or qualifying 
fellow eyes. The use of anti-VEGF agents is not permitted in study eyes or qualifying fellow eyes.
Participants will be instructed not to take minocycline or other tetracycline-class antibiotics for 
any other reason during the study. Participants should avoid taking penicillin while in this study.
Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, 
and preparations that include iron. Participants will be instructed to wait two hours after taking 
their IP before taking one of these antacids.
Participants must not receive methoxyflurane for the duration of the study.
Review of concomitant medications will be conducted with participants at each study visit after 
initiation of IP and recorded.
5.10
Investigational Product Accountability
The indicated pharmacy for each site is responsible for the accountability of all dispensed and 
returned IP. Adequate drug accountability records include documentation of all IP shipped, 
received, dispensed and returned to the indicated pharmacy. The investigator is responsible for the 
accountability of all dispensed IP at their respective site. Adequate drug accountability records 
include documentation of all IP prescribed by the Investigators. Returned IP will be collected and 
stored by each pharmacy in a secure location until reconciliation by the Coordinating Center. 
Following reconciliation by the Coordinating Center, each pharmacy will dispose of returned IP.
5.11
Follow-up/Termination Procedures
At the conclusion of the study, participants will no longer be eligible to receive IP under this 
protocol.
At NEI, follow-up care will be arranged with either an outside ophthalmologist or the participant 
will continue to be seen at the NIH under another protocol if available and if the participant is 
eligible. The participant and his/her physician will be informed of the participant’s disease status 
during this study. Clinical data obtained during participation will be shared with participants and, 
with written permission from the participants, their private physicians. Results from the overall 
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If a participant terminates from the study between study visits, the assessments to be conducted at 
this termination visit will be at the discretion of the investigator. 
5.12
Storage of Samples and Data
No samples will be stored for this study. At the NEI site, the clinical data will be stored in the 
NEI’s electronic medical record (EMR), clinical research information system (CRIS) and 
The Emmes Company, LLC database. At the BEH site, the clinical data will be stored in The 
Emmes Company, LLC’s database.
6.0
RISKS/DISCOMFORTS
The anticipated discomforts and inconveniences of this protocol are those associated with the IP, 
the diagnostic procedures, and the time required for the participant to spend at the clinic.
6.1
Examination Risks
There are risks associated with the procedures required for participants in this study. 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 
pressure will be obtained at each ophthalmic examination to determine whether there is an 
increased risk of developing glaucoma.
2. Stereoscopic color fundus photographs involve a bright flash to take pictures of the retina. 
This brief flash may cause temporary discomfort, but it does not damage the eye.
3. OCT and microperimetry are non-invasive tests used to document and analyze retinal 
pathology and have minimal medical risks.
4. The fluorescein dye used in FA can make a participant’s skin turn yellow for several hours. 
This yellow color is transient and usually disappears in one day. Because the dye undergoes 
renal excretion, the participant’s urine will turn dark orange for up to 24 hours after the 


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examination. The study team will educate the participant regarding this urine color change. 
Some participants may be slightly nauseated during the examination, but their nausea 
usually lasts only a few seconds. If the dye extravasates during the injection, the skin 
around the injection site may feel mildly uncomfortable or become yellow. The discomfort 
usually lasts only a few minutes, and the yellow color fades in a few days. There is a chance 
of ecchymosis at the site of injection and a remote possibility of cellulitis from the needle 
track. In rare cases, participants may have an allergic reaction to the dye. Treatment 
typically consists of an oral antihistamine medication but may require intravenous 
antihistamine administration if the symptoms are severe. Very rarely (less than one in one 
million people), a participant experiences anaphylaxis. This would be treated immediately 
by trained personnel with medications or, if necessary, intubation.
Possible 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, vital signs, review of systems and pregnancy testing entail 
minimal medical risk.
6.1.1
Risks Associated with Minocycline
Risks associated with minocycline are largely associated with oral dosing at a typical dose of 
100mg twice daily. The following adverse reactions have been observed in patients receiving 
typical oral doses of tetracyclines:
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, 
pancreatitis, inflammatory lesions (with monilial over growth) in anogenital region and increases 
in liver enzymes. Rarely, hepatitis and liver failure have been reported. Rare instances of 
esophagitis and esophageal ulcerations have been reported in patients taking the tetracycline-class 
antibiotics in capsule and tablet form. Most of these patients took the medication immediately 
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Skin: Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is 
uncommon. Fixed drug eruptions, including balanitis, have been rarely reported. 
Erythema 
multiforme 
and 
rarely 
Stevens-Johnson 
syndrome 
have 
been 
reported. 
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some 
individuals taking tetracyclines. This has been reported with minocycline. Pigmentation of the skin 
and mucous membranes has been reported.
Renal toxicity: Elevations in blood urea nitrogen (BUN) have been reported and are apparently 
dose related. While this is not a problem in those with normal renal function, in patients with 
significantly impaired function, higher serum levels of tetracycline may lead to azotemia, 
hyperphosphatemia and acidosis. If renal impairment exists, even usual oral or parenteral doses 
may lead to excessive systemic accumulations of the IP and possible liver toxicity.
Hypersensitivity reactions: Urticaria, angioneurotic edema, polyarthralgia, anaphylaxis, 
anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus and rarely 
pulmonary infiltrates with eosinophilia have been reported. A transient lupus-like syndrome has 
also been reported.
Blood: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported.
Central Nervous System: Central nervous side effects including light-headedness, dizziness, or 
vertigo have been reported with minocycline therapy. Headache and blurred vision have also been 
reported. Serious neurologic events reported include bulging fontanels in infants and benign 
intracranial hypertension (Pseudotumor cerebri) in adults. 
Other: When given over prolonged periods, tetracyclines have been reported to produce 
brown-black microscopic discoloration of the thyroid glands. Very rare cases of abnormal thyroid 
function have been reported. Thyroid cancer has been reported in the post-marketing setting in 
association with minocycline products, although the incidence is presently unknown. The internal 
medicine consult service will perform thyroid palpation for Visit 000 and will communicate the 
results to the Investigators. The study investigators will perform the same thyroid palpation as 
outlined in the study flowsheet (Appendix 2). Any clinically significant abnormalities on thyroid 


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palpation and/or thyroid function test (TFT) will prompt a referral to an endocrinologist. 
Decreased hearing has been rarely reported in patients on minocycline hydrochloride. 
Tooth discoloration in children less than eight years of age and, rarely, in adults has been reported. 
Use is not recommended for individuals of either gender attempting child conception. There is a 
risk of impaired spermatogenesis. Because tetracycline can reduce the amount of beneficial forms 
of bacteria in the body, participants will be counseled to include probiotics in their diet while 
participating in the study.
Pregnant and Nursing Women: Minocycline is in Pregnancy Category D and is excreted in 
human milk. Minocycline can cause fetal harm when administered to a pregnant woman. The use 
of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and 
childhood to the age of eight years) may cause permanent discoloration of the teeth 
(yellow-grey-brown).
6.1.2
Drug Interaction-related
Because tetracyclines have been shown to depress plasma prothrombin activity, participants who 
are on warfarin (Coumadin) may require downward adjustment of their anticoagulant dosage. 
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to 
avoid giving tetracycline-class drugs in conjunction with penicillin. Absorption of tetracyclines is 
impaired by antacids containing aluminum, calcium or magnesium, and also preparations that 
include iron. The concurrent use of tetracycline and methoxyflurane has been reported to result in 
fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral 
contraceptives less effective. 
7.0
PARTICIPANT SAFETY MONITORING
Participants will be assessed during each study visit after initiation of IP for AEs by the study 
Investigators. At each visit after initiation of IP, the participant will be asked about any new ocular 
or systemic symptoms including rashes, hospitalizations or new/changed medications. General and 
ophthalmic assessments will be performed according to Appendix 2. Stopping guidelines for 
individual participants and the entire study are outlined below. 


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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 their discretion for the following reasons:

Investigator determination that it is not in the best medical interest of the participant to 
continue participation;

Findings in the course of the trial that may affect willingness to participate;

The development of AMD-related CNV in the study eye of the participant;

Participant requires additional medicines or subconjunctival or intravitreal injections that 
will interfere with the IP;

Pregnancy;

Serious suspected adverse reaction;

VA loss of >30 letters from initial study visit;

Any other safety concerns;

Inability to keep study visits or to comply with study requirements.
Discontinuation of IP does not require participant withdrawal from the protocol. If the participant 
agrees to continue in the study after discontinuing IP, s/he will continue to return for their 
subsequent study visits and undergo the required examinations. Otherwise, the participant will exit 
the study and continue his/her ophthalmic care either with an outside ophthalmologist or at the 
NEI. Participants will be monitored by study Investigators and clinical staff at each visit to the 
clinic.
7.2
Pregnancy Monitoring
If an investigator becomes aware that a female study participant has become pregnant during the 
study, the investigator will advise the participant to stop taking the IP immediately. 
The investigator and participant will determine whether to continue any remaining study visits or 
to exit the study.


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If an investigator becomes aware that a male study participant has impregnated his partner during 
the study, 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. The data must be recorded on the 
Confirmed Pregnancy and Outcome form in the Electronic Medical Record (EMR), which is also 
reported to the Coordinating Center.
8.0
OUTCOME MEASURES
8.1
Primary Outcome
The primary outcome is the difference in the rates of GA area expansion in the study eye between 
the run-in phase of the study and following IP initiation. GA area determination will be based on 
digital grading of FAF images by an external Reading Center. The primary outcome will be the 
difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of treatment 
(Month 33) compared to initial study visit (Month 0) to IP start visit.
8.2
Secondary Outcomes
Secondary outcomes will examine the differences in the rates of outcome measure progression in 
the study eyes between the run-in phase of the study and following IP initiation. These outcome 
measures include: GA area expansion based on FAF images by an external Reading Center using 
a different statistical approach compared to primary outcome, GA area expansion based on digital 
grading of color fundus images by an external Reading Center, changes in BCVA, changes in low 
luminance VA, changes in central retinal thickness on OCT. Measures obtained from qualifying 
fellow eyes (i.e., fellow eyes of participants that also meet eye-specific eligibility criteria) will also 
be analyzed separately and together with study eyes as secondary outcome measures. 
8.3
Exploratory Outcome
The exploratory outcome will compare the difference in the rate of change in macular sensitivity 
as measured using microperimetry. This outcome was originally a secondary outcome when the 
clinical trial participants were enrolled, since these represent visual function data corresponding 


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closely to areas affected by geographic atrophy. Hence, changes in microperimetry data over time 
might be well placed to support changes in structural data over time, as geographic atrophy lesions 
undergo enlargement. In the original Statistical Analysis Plan, the intention was that 
“Macular sensitivity, as measured on microperimetry, will be evaluated in a similar manner as 
BCVA”, (i.e., “Mean rate of change in BCVA during the treatment phase will be compared to the 
mean rate of change in BCVA during the run-in phase using Student’s paired t-test”). 
However, microperimetry data (represented by multiple numerical values, one for each anatomical 
location, at each time-point) are much more complex than BCVA data (represented by a single 
numerical value at each time-point). The originally proposed statistical treatment is therefore not 
suitable. In addition, the study team is not aware of any established methods accepted by the 
community for analyzing microperimetry data, unlike the situation for BCVA. Indeed, the 
microperimetry acquisition pattern used in GA MIN is unique and was developed specifically for 
this trial. It therefore needs its own dedicated set of statistical analyses (which may need several 
iterations), rather than pre-specified and widely accepted analyses that could be detailed in advance 
in the Statistical Analysis Plan. For these reasons, although the original intention was for the 
microperimetry data to represent a secondary outcome measure, it is better suited as an exploratory 
outcome measure. 
8.4
Ocular Safety Outcomes
Ocular safety outcomes will be indicated by changes in VA, ocular surface changes, intraocular 
inflammation and any other ocular changes not consistent with the natural progression of GA.
9.0
STATISTICAL ANALYSIS
All participants will be followed throughout the duration of the study and included in the analyses.
9.1
Study Design and Primary Analysis
Rate of change in GA, based on digital grading of FAF, will be monitored throughout the study 
period in both the study and fellow eyes. A spline regression model with a fixed knot at Month 9 
will be computed to compare the rates of change in GA from IP start visit to 24 months of treatment 
and from initial study visit to IP start visit in the study eyes of all participants (49). 
Spline regression is a linear modeling method used to assess the longitudinal effects of an 


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intervention on an outcome of interest (49). Splines require at least one break in the study time 
period, a knot. This knot represents a specific point in time that is hypothesized to be the starting 
point of change from the previous, established trend (49), (50).
The spline regression model will compute the slopes for the run-in period and for the treatment 
period. This method will allow for the comparison of the two slopes and will test whether the 
slopes are significantly different (50). A square-root transformation will be used in an attempt to 
satisfy the linear trend assumption of the spline regression model (Box-Cox or logarithm 
transformations may also be attempted if a square-root transformation does not achieve a sufficient 
linear trend). Ninety-five percent confidence intervals for the rate of change and difference in rates 
will also be calculated–based on the transformed data and back transformed to the rate scale.
9.2
Handling Data Irregularities
Although the study will make efforts to ensure maximum participant compliance, data 
irregularities, including protocol deviations, noncompliance, withdrawals, missing values and 
losses to follow-up, may occur and will impact the proposed analyses. These analyses will be 
conducted on all participants enrolled in the study, regardless of compliance, follow-up or 
treatment received. Since the primary outcome is a rate of change, all available FAF data from 
participants who discontinue from the study prior to their Month 9 or 33 study visit will be modeled 
with a longitudinal within-participant linear regression model. This model will determine each 
participant’s annualized rate of progression (i.e., slope of regression line for FAF area over time).
Sensitivity of the data based on the above population to missing observations will be assessed by 
comparing the results with Multiple Imputation (MI) analysis and the treatment-received analysis 
based on the Per Protocol (PP) population (without missing observations). In the MI analysis, 
participants’ post-treatment data will be utilized in a longitudinal regression model to estimate 
annualized rate of progression. This analysis assumes that GA progression rates are similar pre 
and post-study withdrawal. In the MI analysis, MI method will be used to generate many different 
annualized progression rates for participants who withdraw early. More specifically, the MI 
procedure will 1) generate multiple imputed datasets (approximately 2,000); 2) perform a t-test for 
each dataset; and 3) finally combine t-values with standard errors that reflect the uncertainty 


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inherent in imputation. Under the assumption that the transformation of the rates of change in area 
of GA are normally distributed, the missing rates from the run-in phase and the treatment phase 
will be predicted from each participant’s observed area of GA, and scheduled visits and joint 
relationships with other variables (e.g. participant’s age, visual acuities, OCT measurements).
The final analysis for the longitudinal data throughout the follow-up will treat missing observations 
completely at random (MCAR).
Participants’ compliance with IP administration will be assessed through capsule counts during 
study visits. If study IP compliance falls below 80% of the level prescribed for any participant, the 
participant will be queried about the reasons for decreased compliance and counseled on the 
importance of compliance for study integrity. The level of compliance will be reported to the IRB 
on annual review and taken into account in the analyses of study outcomes. To ensure the study is 
not biased by IP noncompliance, statistical analyses will look at the associations between IP 
compliance, dropout, and treatment effect during Months 12, 15, and 21. If IP compliance cannot 
be determined for a participant during any visit, IP compliance will be imputed by taking the 
median of all capsule counts recorded at previous study visits.
9.3
Analysis of Secondary Endpoints
Any participant who completes three or more visits during the treatment phase will be included in 
these analyses.
VA will be evaluated in both the study and fellow eyes at each scheduled visit, with the secondary 
outcome defined as a three-line worsening in BCVA. A change from initial study visit of 15 letters 
score (three lines) or more, is considered clinically significant. Mean change in BCVA during the 
treatment phase will be compared to the run-in phase.
Development of wet AMD as measured by OCT will be monitored throughout the study period in 
both the study and fellow eyes. Absolute and relative changes in GA will be assessed using fundus 
photography and FAF imaging throughout the study period.


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Safety outcomes, including the number and severity of AEs will be tabulated by severity, type and 
assessed relatedness to the IP. The number of participants withdrawn from the IP due to vision 
loss, AEs and treatment failure will also be tabulated.
These analyses will be descriptive and will include tabulations of outcomes over the study period. 
Some nonparametric analyses may be utilized for exploratory analyses of secondary endpoints.
9.4
Sample Size/Accrual Rate
The accrual goal is to enroll 45 participants, approximately 20 at NEI and 25 at BEH. 
This sample size was determined for the primary analysis of the difference in rate of change in 
square-root transformed GA area in the study eye between IP start visit to 24 months of treatment 
and initial study visit to IP start visit. A two-sided paired t-test at an alpha level of 0.05, comparing 
square-root transformed rates of change in GA between 24 months of treatment and the run-in 
phase was employed.
A rate of 1.52 mm2/year is assumed for the run-in phase in the current study, based on the median 
GA expansion rates suggested in the literature (45). For data that are skewed, the square-root of 
the mean is not equal to the mean of the square-root transformed data. However, since a quantile 
of strictly positive data is invariant to transformation (e.g., the square-root of a given quantile of 
the original observations is equal to that quantile of the transformed observations), and for 
symmetric data mean and median are equal, the square-root of the median progression rate 
(√1.52 mm2/year = 1.23 mm/year) is used to approximate the assumed mean progression rate for 
the square-root transformed run-in phase. The treatment phase is assumed to have a 25% reduction 
in the GA growth rate, equivalent to a 13% reduction of the square-root transformed rate, implying 
a mean progression rate of 1.07 mm/year for the square-root transformed GA growth rate during 
the treatment phase. A standard deviation of 0.30 mm/year was obtained from previous NEI GA 
protocols exploratory analyses data and was assumed for the GA growth rate during the run-in 
phase. Given the strictly positive nature of GA enlargement, a reduction in mean progression rate 
during the treatment phase necessitates a smaller standard deviation. However, on the square-root 
scale, the difference in standard deviations between the run-in and treatment phases is negligible 
for the proposed 25% reduction in means, and a standard deviation of 0.30 was also assumed for 


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the square-root transformed GA growth rate during the treatment phase. Since this is a single arm 
study utilizing each participant as their own control, measurements will be highly correlated 
between the run-in and treatment phases. A correlation of 0.8 was used to account for the high 
dependence in measurements between the run-in and treatment phases. Since the study population 
consists of older adults, loss to follow-up due to various reasons is expected and needs to be taken 
into account for an accurate sample size. Based on these square-root transformed mean and 
standard deviation estimates, a sample size of at least 17 participants is required to obtain at least 
90% power to detect a difference in progression rates if the true square-root transformed 
progression rates are 1.23 mm/year during the run-in phase and 1.07 mm/year during the treatment 
phase of 24 months, with an 80% within-in participant correlation. Approximately 12 months will 
be necessary to accrue these participants. After the first 15 participants have reached their 
Month 9 visit, the study dropout rate will be assessed and a sample size re-estimation may be 
performed.
Sunness, et al. (46), (45) state that a sample size of 306 is necessary to detect a treatment effect of 
25% when examining the effect of a new systemic treatment on GA growth rate in individuals 
(46). One of the factors that resulted in the reduction of sample size from the Sunness suggestion 
is the use of FAF instead of CFP to grade GA. FAF appears to be more precise (i.e., lower 
within-patient SD) than CFP. For example, the coefficient of variation for the square-root 
transformed FAF data is 2.5, while the coefficient of variation for the CFP data summarized in 
Sunness is 1.3. Further, the current study design utilizes each participant as their own control, 
significantly decreasing within-participant variability and the need for a large sample size.
10.0
HUMAN PARTICIPANTS PROTECTION
10.1
Equitability
Accrual will be equitable for this study. Minimum age of participation was set at 55 years as GA 
in the context AMD does not typically occur in patients younger than this age; including patients 
< 55 years old will increase the risk of enrolling “masqueraders” (i.e., patients with clinical 
findings similar to GA but arise from a different etiology).


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10.1.1 Justification for Exclusion of Children
Children will not be eligible for this study, as the condition under study affects primarily adults.
10.1.2 Justification for Exclusion of Pregnant or Lactating Women
Pregnant or lactating women are not eligible for this study because of the known and unknown 
risks of minocycline. One of the known risks of minocycline is that it can cause permanent 
discoloration of the teeth (yellow-grey-brown) of a fetus when given to a pregnant woman during 
the last half of pregnancy. Minocycline also passes into breast milk and can cause permanent 
discoloration of the teeth of a nursing infant. Given the known and unknown effects on pregnancy 
outcomes, two forms of contraception will be required for female participants of childbearing 
potential (see Appendix 1 for definition). In addition, female participants of childbearing potential 
will undergo urine pregnancy tests throughout the study.
10.1.3 Refraction and Visual Acuity
Specific certification in EVA techniques for refraction and visual acuity determinations is required 
for this study. Certification involves a practicum and testing in the competent use of the technique 
and the proper recording of the data. Each person (e.g., physician, optometry professional, 
ophthalmic technician and/or nurse) that performs these determinations on study participants must 
be certified. If necessary, training and certification in the EVA methods can be provided prior to 
study initiation. The Coordinating Center must review and approve any training or certifications 
not conducted by Emmes staff. Emmes may grandfather existing certifications if candidates are 
currently certified for similar procedures in other NEI studies and have been actively performing 
the EVA refraction and visual acuity testing protocol.
10.1.4 Photography Qualification
DIRRL will qualify the site to perform OCT, FAF, color fundus photography, and microperimety 
imaging as specified in the DIRRL Study Instruction Manual.


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10.1.5 Professional Licensure
Physicians must provide evidence of current medical licensure applicable to the study location(s) 
if they are practicing medicine and undertake to diagnose and/or treat participants (including 
administration of the investigational product) in this study. A physician who is a site PI must also 
provide satisfactory evidence of ophthalmology training before study initiation.
11.0
ANTICIPATED BENEFIT
Participants may benefit directly from this study if study drug decreases the progression of GA 
and preserves VA. The study will also lead to generalizable knowledge that will enhance our 
understanding of using minocycline as treatment for participants with GA associated with AMD.
12.0
CONSENT DOCUMENTS AND PROCESS
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, 
and they will be informed that they may withdraw from the study at any time without prejudice to 
themselves. 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 copy of the signed informed consent form will be provided to the 
participant to take home.
13.0
DATA AND SAFETY MONITORING
The PI and the NEI DSMC are responsible for monitoring data and safety and will exercise 
oversight of the clinical investigation independently from the study Investigators.


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13.1
Coordinating Center
Emmes 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.
Communications between the investigational site and the Coordinating Center will be maintained 
through regular telephone and e-mail contacts between the Coordinating Center Protocol Monitor 
and the site PI and/or Coordinator. Substantive communications must be maintained both at the 
site and at the Coordinating Center containing the date and a summary of communications where 
instructions are given or received, an interpretation of protocol requirements is made, 
recommendations for corrections to study documentation are made, or where the reporting of 
possible AEs is discussed.
Although the Coordinating Center advises the NEI Clinical Director (CD) and PI on data and 
statistical activities, the Coordinating Center staff does not have direct access to or interaction with 
participants.
13.2
Data and Safety Monitoring Committee
The NEI DSMC is responsible for reviewing and approving the study design and, as appropriate, 
recommending design changes. In addition, the DSMC assesses study data with particular 
consideration of participant safety. The DSMC will convene prior to the initiation of the trial to 
review the protocol. Emmes will provide accumulated data from all study sites to the NEI DSMC. 
The Committee will review accumulated data at minimum twice a year but will convene ad hoc 
meetings to address any significant problems related to participant safety brought to its attention 
by any study participant or investigator. The Committee will review the accumulated data and 
consider whether a protocol modification is necessary and approve protocol modifications. 
If changes in protocol are indicated, recommendations will be made to the NEI Director and CC 
Director who will consider and act on such recommendations in a timely manner.


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13.3
Criteria for Stopping the Study
The DSMC 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 (SAEs), etc.).
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 DSMC 
(if applicable).
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. Per the monitoring 
plan, the frequency of interim monitoring visits is every six months from enrollment through the 
end of participant follow-up. Site visit frequency modifications may be made to accommodate 
increases or decreases in the quantity of data requiring review and as deemed necessary by the 
Sponsor and coordinating center, with the minimum site monitoring frequency to occur no less 
than annually. In addition to monitoring, Emmes performs various detailed automated and manual 
data quality checks on an ongoing basis. The results from these checks and any protocol 
compliance issues are communicated back to site staff and to the NEI Project Officer, NEI CD and 
applicable regulatory bodies.


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15.0
REPORTABLE EVENTS
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801.
16.0
ALTERNATIVES TO PARTICIPATION
High-dose vitamin supplementation can reduce the progression to exudative AMD (12). 
Participants will be allowed to take AREDS-type vitamin supplements during the course of the 
trial. Currently, there are no other treatments which have been approved for the treatment of GA 
in AMD. Therefore, participants do not forego any known effective treatments and the alternative 
is not to participate in the study. Participants can alternatively receive minocycline outside of the 
study if prescribed off-label by their own physician.
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 Emmes. Only study Investigators and Emmes 
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, coded identifier and study registration 
number will identify the participant if their information is shared with the Coordinating Center for 
research purposes. 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, the Coordinating Center and the NEI DSMC.
19.0
CONFLICT OF INTEREST
The NIH guidelines were distributed to all the Investigators and none of the Investigators had any 
conflicts of interest.
20.0
TECHNOLOGY TRANSFER
There are no technology transfer agreements for this study.


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21.0
RESEARCH AND TRAVEL COMPENSATION
For this study, there is no compensation for participation. This protocol includes reimbursement 
for travel, accommodation, and subsistence. At the NEI, 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
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Zeng HY, Zhu XA, Zhang C, Yang LP, Wu LM, Tso MO. Identification of sequential 
events and factors associated with microglial activation, migration, and cytotoxicity in retinal 
degeneration in rd mice. Invest Ophthalmol Vis Sci. 2005;46(8):2992-9.
39.
Hughes EH, Schlichtenbrede FC, Murphy CC, Broderick C, van Rooijen N, Ali RR, et al. 
Minocycline delays photoreceptor death in the rds mouse through a microglia-independent 
mechanism. Exp Eye Res. 2004;78(6):1077-84.
40.
Yang LP, Li Y, Zhu XA, Tso MO. Minocycline delayed photoreceptor death in rds mice 
through iNOS-dependent mechanism. Molecular vision. 2007;13:1073-82.
41.
Salamon SM. Tetracyclines in ophthalmology. Surv Ophthalmol. 1985;29(4):265-75.
42.
Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin 
Ther. 2005;27(9):1329-42.
43.
Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline 
treatment in acute stroke: an open-label, evaluator-blinded study. Neurology. 2007;69(14):1404-
10.
44.
Cukras CA, Petrou P, Chew EY, Meyerle CB, Wong WT. Oral minocycline for the 
treatment of diabetic macular edema (DME): results of a phase I/II clinical study. Investigative 
ophthalmology & visual science. 2012;53(7):3865-74.


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45.
Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-
Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns 
in age-related macular degeneration. Am J Ophthalmol. 2007;143(3):463-72.
46.
Sunness JS, Margalit E, Srikumaran D, Applegate CA, Tian Y, Perry D, et al. The long-
term natural history of geographic atrophy from age-related macular degeneration: enlargement of 
atrophy and implications for interventional clinical trials. Ophthalmology. 2007;114(2):271-7.
47.
Choudhry N, Giani A, Miller JW. Fundus autofluorescence in geographic atrophy: a 
review. Seminars in ophthalmology. 2010;25(5-6):206-13.
48.
The Age Related Eye Disease Study 2 Research Group (AREDS2), Chew E, Clemons T, 
SanGiovanni J, Danis R, Ferris Fr, et al. Lutein + zeaxanthin and omega-3 fatty acids for age-
related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized 
clinical trial. Jama. 2013;309(19):2005-15.
49.
Wagner A, Soumerai S, Zhang F, Ross-Degnan D. Segmented regression analysis of 
interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27:299-309.
50.
Fitzmaurice G, Laird N, Ware J. Modeling the Mean: Parameteric Curves. Applied 
Longitudinal Analysis. 2011;2nd ed,pp. 149-151. Hoboken, NJ: Wiley.


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APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL
A female 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 female participant is considered non-childbearing due to menopause, it must be in accordance 
with the NIH OB-GYN guidance on the definition of menopause. This guidance defines 
menopause as:

Women 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.

Women age 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.


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APPENDIX 2: STUDY FLOWSHEET
Run-in Phase
Treatment Phase
Visit Schedule1 (Month)
0
3
6
9
12
15
21
27
33
39
45
512
572
Visit Number
000
003
006
009
012
015
021
027
033
039
045
051
057
Target Visit Day
0
90
180
272
365
455
637
820
1002
1190
1371
1555
1735
Treatment5
Dispense Investigational Product 
(taken twice daily)3
X
X
X
X
X
X
X
X4
X4
X4
Drug Accountability Review
X
X
X
X
X
X
X
X
X
General Assessments5
Medical/Ophthalmic History
X
Concomitant Medications 
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
Thyroid Palpation6
X
X
X
X
X
X
X
X
X
X
Physical Examination
X8
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
Ophthalmic Assessments5
BCVA (EVA)
X9
X
X
X
X
X
X
X
X
X
X
X
X
Manifest Refraction
X9
X
X
X
X
X
X
X
X
X
X
X
X
Low-luminance visual acuity10
X9
X
X
X
X
X
X
X
X
X
X
Slit Lamp Examination
X9
X
X
X
X
X
X
X
X
X
X
X
X
Dilated Fundus Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Intraocular Pressure (IOP)
X9
X
X
X
X
X
X
X
X
X
X
X
X
Stereoscopic Color Fundus 
X7
X
X
X
X
X
X
X
X
X
X
X
X
Fundus Autofluorescence (FAF) 
and Infrared Reflectance Imaging
X7
X
X
X
X
X
X
X
X
X
X
X
X


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Run-in Phase
Treatment Phase
Visit Schedule1 (Month)
0
3
6
9
12
15
21
27
33
39
45
512
572
Visit Number
000
003
006
009
012
015
021
027
033
039
045
051
057
Target Visit Day
0
90
180
272
365
455
637
820
1002
1190
1371
1555
1735
Microperimetry 12
X7
X
X
X
X
X
X
X
X
X
X
Optical Coherence Tomography 
(OCT)
X7
X
X
X
X
X
X
X
X
X
X
X
X
Fluorescein Angiography
X13
Laboratory Assessments5,8
Acute Care Panel
X8
X
X
X
X
X
X
X
X
X
Hepatic Panel
X8
X
X
X
X
X
X
X
X
X
Complete Blood Count (CBC)
X8
X
X
X
X
X
X
X
X
X
Thyroid Function Test (TFT)
X8
X
X
X
X
X
X
X
X
X
Pregnancy Test11
X8
X
X
X
X
X
X
X
X
X
1
All visits must be conducted within a window of ±30 days from the target visit day.
2
These visits are for participants who enrolled at the beginning of the study and continue until the common termination date. The common termination date is 
reached when the last recruited participant has received 36 months of IP. Participants may complete participation in the study as early as Month 45, at the 
discretion of the investigator. Participants who complete the Month 57 visit may terminate the study at the same visit or return for a final (supplemental) visit to 
terminate from the study. 
3
Participants will take an IP capsule two times a day, once in the morning and once in the evening, approximately 12 hours apart. At the time the IP is dispensed, 
an information sheet outlining instructions on taking IP and concomitant medications will be provided to the participant.
4
IP will only be dispensed at these visits for participants who enrolled at the beginning of the study and continue IP until the common termination date. If a 
participant is terminating at this visit, IP will not be dispensed. 
5
In the event that the testing was not completed within a day, subsequent clinic visits may be scheduled within 10 days of the first visit to complete the scheduled 
evaluation.
6
The internal medicine consult service will perform the thyroid palpation for Visit 000 and will communicate the results to the Investigators. The study 
Investigators will perform the same thyroid palpation at each study visit, beginning at Month 9. Any clinically significant abnormalities on thyroid palpation 
and/or TFT will prompt a referral to an endocrinologist.


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7
Indicated assessment may be performed under NIH Protocol 08-EI-0102, NIH Protocol 08-EI-0169, NIH 08-EI-0043, NIH 12-EI-0042, or NIH 11-EI-0147 if 
performed within 30 days prior to the initial study visit.
8
Indicated assessment may be performed under NIH Protocol 08-EI-0102, NIH Protocol 08-EI-0169, NIH 08-EI-0043, NIH 12-EI-0042, or NIH 11-EI-0147 if 
performed within 60 days prior to the initial study visit.
9
If the indicated assessment was previously performed under NIH Protocol 08-EI-0102, NIH Protocol 08-EI-0169, NIH 08-EI-0043, NIH 12-EI-0042, or NIH 
11-EI-0147 for screening, the assessment will be repeated at time of enrollment.
10 The procedure will be performed on study eye and the qualifying fellow eye. Evaluations on non-qualifying fellow eyes may be performed for routine clinical 
evaluation for the continuing care of the participant as determined by the treating investigator.
11 For women of childbearing potential only, participants must have a negative pregnancy test within 24 hours prior to dispensation of IP. See Appendix 1 for 
guidance on determining whether a female is considered to be of childbearing potential.
12 Mesopic microperimetry will be performed on study eyes and scotopic microperimetry will be performed on qualifying fellow eyes. If a participant is unable to 
complete microperimetry testing, the testing may be waived for subsequent study visits and the investigator will specify the reason the test could not be completed.
13 FA will only be performed if the absence of CNV cannot be definitively ascertained after review of retinal images. 


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APPENDIX 3: GEOGRAPHIC ATROPHY GRADING PROCEDURES FROM 
DIGITIZED PHOTOGRAPHS
GA will be assessed from the color fundus photographs. GA is observed as one of more sharply 
defined patches of partial or complete depigmentation of the retinal pigment epithelium (RPE), 
typically with exposure of underlying large choroidal blood vessels. In general at least two of the 
aforementioned characteristics (sharp edges, more or less circular shape and visibility of 
underlying choroidal vessels) are required for a lesion to be classified as GA. Thus, even if much 
of the RPE appears to be preserved and large choroidal vessels cannot be seen, a roundish patch 
of RPE depigmentation with sharp edges may still be classified as GA. The criterion of “edge 
sharpness” may be fulfilled in either of two ways: (1) when the depigmentation within the patch 
is subtle, a “sharp” edge must be abrupt and smooth, like one made with a cookie cutter, or 
(2) when contrast between depigmentation within a patch and the normal depigmentation around 
it is substantial, the edge of the patch may still be considered “sharp” even if the transition occurs 
gradually or irregularly over a zone of 125 to 250 µm in width. Increased visibility of large 
choroidal vessels is the single most important criterion and, when present, it is not necessary for 
all the edges of the patch to be sharp (25% of its circumference may be sufficient).
Longitudinal analysis of each patient is performed as a quality control measure in order to ensure 
consistency in borderline decisions regarding the extent of GA.
Once GA has been identified on the FAF by the grader, the grader will manually outline the GA 
lesion(s) using the Doheny Image Reading & Research Lab GRADOR software. All areas of GA 
will be outlined. Then, using the results generation function of the GRADOR, the pixel counts 
within the outlined area(s) will be converted to areas, in units of both MPS DA and mm2.


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APPENDIX 4: PARTICIPANT REMINDERS
Participant Reminders
1. On the day of your fourth visit, you will receive your first supply of your study medication. 
On that day, you will take one pill in the evening. On the next day and all other days of the 
study, you will take two pills every day, one in the morning and one in the evening. Take them 
at approximately the same time every day, approximately 12 hours apart, to help you to 
remember to take them.
2. Take your pills with a full glass (eight ounces) of water or more.
3. Do not take iron, multivitamins, calcium supplements, antacids or laxatives within two hours 
before or after taking your study medication. These products may make your study medication 
less effective. 
4. If you vomit after taking your pill, do not repeat a dose. Contact the Principle Investigator or 
NEI Study Coordinator about vomiting or ANYTHING else that you feel is a side effect.
5. If you forget to take a pill and it is less than six hours after the missed dose, you should take 
the pill when you remember and take the next dose at your regularly scheduled time. If you 
forget to take a pill and it is more than six hours after the missed dose, you should skip that 
dose and take the next dose at your regularly scheduled time. 
6. Your pills should be stored at room temperature (59 - 86° F). They should be protected from 
light, moisture, and excessive heat.
7. Please inform any doctor who is prescribing new medication that you may be taking 
minocycline. If a new medication is prescribed to you, please inform a study team member at 
your next visit. If you are prescribed any new antibiotics, please contact a study team member 
immediately.
Please be aware that minocycline can reduce or prevent some medications from working. 
Medications, such as penicillin, may not work when taking minocycline.
8. Remember to bring your pill bottles and any leftover pills with you to all appointments.
9. We will supply you with study medication at every visit. If for any reason you miss a study visit, 
contact a member of the study team so that your appointment can be rescheduled and 
arrangements made to supply you with your study medication. 
10. If you develop diarrhea while you are enrolled in this study, seek medical attention promptly. 
11. While taking this study medicine, you should: 

Wear protective clothing, including a hat and sunglasses whenever you are outside. 

Apply a sun block product that has a skin protection factor (SPF) of at least 15 to your skin 
and a sun block lipstick to your lips. Those who have a fair complexion should use sunblock 
with a higher SPF number. 

Use extra caution near water, snow and sand because they reflect and intensify the 
damaging rays of the sun.


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
Not use a sunlamp or tanning bed or booth.
You may still be more sensitive to sunlight or sunlamps for two weeks to several months or 
more after stopping this medicine. If you have a severe reaction, see your doctor immediately.
12. Remember, if you are a woman who is able to get pregnant or if you are a man able to father 
children, you (or your partner) must have had a hysterectomy or a vasectomy, be completely 
abstinent from intercourse or be willing to use two effective methods of birth control while in 
this study and for one week after you stop taking the study pills.
Please be aware that minocycline can make hormonal contraceptives less effective and 
increase the risk of pregnancy. 
Acceptable methods of birth control for this study include the combined use of TWO of the 
following methods:
1. hormonal contraception (birth control pills, injected hormones, skin patch or vaginal ring), 
2. intrauterine device 
3. diaphragm with spermicide or a condom with spermicide, or
4. tubal ligation.
A gynecologist will advise you on the acceptable methods of birth control.
Contact your study team with any questions:
Study Coordinator: 
NAME
CONTACT NUMBER
Principal Investigator:
NAME
CONTACT NUMBER
Please note: If any questions or issues arise after normal business hours or on the weekend, you 
may call EMERGENCY AFTER HOURS CONTACT. Be sure to identify the study you are on.
YOUR STUDY IS: 15-EI-0202
“Pilot Study for the Evaluation of Oral Minocycline in the Treatment of Geographic Atrophy 
Associated with Age-Related Macular Degeneration”

SAP_001.pdf: 
Restricted 
Statistical Analysis Plan 
for 
Evaluation of Oral Minocycline in the Treatment of Geographic Atrophy Associated with 
Age-Related Macular Degeneration (GA) 
 
15-EI-0202 
NCT02564978 
 
Version 4.0 
March 21, 2023 
 
Prepared by 
 
 
 
 
Original Author Signature: 
 
 
 
 
 
 
 
Reviewer Signature:  
 
 
 
 
 
 
 
Principal Investigator Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GA MIN SAP 
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TABLE OF CONTENTS  
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Page i 
TABLE OF TABLES ..................................................................................................................................... III 
TABLE OF LISTINGS ................................................................................................................................... IV 
TABLE OF FIGURES .................................................................................................................................... IV 
VERSION HISTORY ....................................................................................................................................... V 
LIST OF ABBREVIATIONS .......................................................................................................................... VI 
1.0 
INTRODUCTION ............................................................................................................................. 1 
1.1 
Age-related Macular Degeneration (AMD) ................................................................................... 1 
1.2 
Treatment of Age-related Macular Degeneration ........................................................................... 2 
1.3 
Geographic Atrophy ....................................................................................................................... 2 
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 
3.3.2 
Study Eye Eligibility Criteria .................................................................................................. 6 
3.4 
Outcomes ........................................................................................................................................ 8 
3.4.1 
Primary Study Outcome .......................................................................................................... 8 
3.4.2 
Secondary Study Outcomes .................................................................................................... 8 
3.4.3 
Safety Outcomes ..................................................................................................................... 9 
4.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 9 
4.1 
Sample Size Calculation ................................................................................................................. 9 
4.2 
Sample Size Re-estimation ........................................................................................................... 11 
4.3 
Analysis Populations .................................................................................................................... 11 
4.4 
Study Phases ................................................................................................................................. 12 
4.5 
Descriptive Statistics .................................................................................................................... 12 
4.6 
Statistical Tests and Adjustments for Multiple Comparisons ....................................................... 12 
4.7 
Handling Duplicate Assessments ................................................................................................. 13 
4.8 
Software for Analyses .................................................................................................................. 13 
5.0 
PARTICIPANT DISPOSITION ........................................................................................................ 13 
6.0 
PARTICIPANT CHARACTERISTICS .............................................................................................. 14 
6.1 
Participant Demographics ............................................................................................................ 14 
6.2 
Medical and Ocular History ......................................................................................................... 14 
7.0 
PARTICIPANT COMPLIANCE ....................................................................................................... 14 
7.1 
Protocol Deviations and Unanticipated Problems ........................................................................ 14 
7.1.1 
IP Compliance Deviations ..................................................................................................... 15 
7.1.2 
Study Procedure Deviations .................................................................................................. 16 
7.1.3 
Visit Schedule Deviations ..................................................................................................... 16 
7.2 
Premature Treatment and Study Withdrawals .............................................................................. 17 
8.0 
PRIMARY OUTCOMES ANALYSIS ............................................................................................... 17 
9.0 
SECONDARY OUTCOMES ANALYSIS........................................................................................... 18 
9.1 
Area of GA based on Fundus Autofluorescence (FAF) ............................................................... 18 
9.2 
Area of GA based on Color Fundus Photos (CFP) ....................................................................... 19 
9.3 
Best-Corrected Visual Acuity (BCVA) ........................................................................................ 20 
9.4 
Low Luminance Visual Acuity (LLVA) ...................................................................................... 20 
9.5 
Central Retinal Thickness ............................................................................................................. 21 
10.0 
SENSITIVITY ANALYSES .............................................................................................................. 21 


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TABLE OF CONTENTS (CONTINUED) 
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11.0 
EXPLORATORY ANALYSES ......................................................................................................... 21 
12.0 
OCULAR SAFETY OUTCOMES ..................................................................................................... 23 
12.1 Best-Corrected Visual Acuity (BCVA) ........................................................................................ 23 
12.2 Ocular Surface Changes and Inflammation .................................................................................. 24 
13.0 
OTHER SAFETY OUTCOMES ....................................................................................................... 24 
13.1 Adverse Events (AEs) .................................................................................................................. 24 
13.2 Withdrawal from IP Due to Vision Loss, Adverse Events, and Treatment Failure ..................... 25 
13.3 Low-Luminance Visual Acuity (LLVA) ...................................................................................... 25 
13.4 Intraocular Pressure (IOP) ............................................................................................................ 25 
13.5 FAF Assessments ......................................................................................................................... 25 
13.6 CFP Assessments ......................................................................................................................... 26 
13.7 OCT Assessments ......................................................................................................................... 26 
13.8 Physical Examination, Thyroid Palpation, Intracranial Hypertension, CNV and Optic Nerve 
Swelling ........................................................................................................................................ 27 
13.9 Laboratory Assessments ............................................................................................................... 27 
13.10 Other Safety Outcomes ................................................................................................................. 27 
14.0 
RATIONALE FOR ANY DEVIATION FROM PRE-SPECIFIED ANALYSIS PLAN ........................... 27 
15.0 
QUALITY ASSURANCE PLANS ..................................................................................................... 28 
16.0 
REFERENCES ............................................................................................................................... 29 
17.0 
MOCK SHELLS ............................................................................................................................. 31 
18.0 
PRIMARY OUTCOME ANALYSIS PRESENTATIONS .................................................................... 62 
 


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TABLE OF TABLES 
Table 1. Participant Disposition .................................................................................................................. 31 
Table 2. Summary of Demographic Characteristics ................................................................................... 33 
Table 3. Medical and Ocular History .......................................................................................................... 34 
Table 4. Summary of Participant-Specific Protocol Deviations and Unanticipated Problems ................... 35 
Table 5. Summary of Non-Participant Specific Protocol Deviations and Unanticipated Problems ........... 36 
Table 6. IP Compliance ............................................................................................................................... 37 
Table 7. Missed Study Procedures .............................................................................................................. 38 
Table 8. Missed and Out of Window Study Visits ..................................................................................... 39 
Table 9. Analysis of Primary Outcome of Difference in Rates of Change in Appropriately Transformed 
GA Area During Run-in and Treatment Phases as Determined Using FAF Images and 
Corresponding Sensitivity and Exploratory Analyses ................................................................. 40 
Table 10. Analysis of Secondary Outcome of Difference in Rates of Change in Appropriately 
Transformed GA Area During Run-in and Treatment Phases as Determined Using FAF Images 
and Corresponding Exploratory Analyses ................................................................................... 41 
Table 11. Analysis of Secondary Outcome of Difference in Rates of Change in Appropriately 
Transformed GA Area During Run-in and Treatment Phases as Determined Using CFP and 
Corresponding Exploratory Analyses ......................................................................................... 42 
Table 12. Analysis of Secondary Outcome of Change in BCVA ............................................................... 42 
Table 13. Analysis of Secondary Outcome of Change in LLVA................................................................ 43 
Table 14. Analysis of Secondary Outcome of Change in Central Retinal Thickness on OCT ................... 43 
Table 15. Summary of BCVA Total Letters Read Over Time ................................................................... 44 
Table 16. Summary of Ocular Surface Changes and Inflammation Over Time ......................................... 45 
Table 17. Summary of Treatment-Emergent Adverse Events .................................................................... 45 
Table 18. Summary of Treatment-Emergent Adverse Events by System Organ Class (SOC) and Preferred 
Term (PT) .................................................................................................................................... 46 
Table 19. Summary of LLVA Total Letters Read Over Time .................................................................... 46 
Table 20. Summary of IOP Over Time ....................................................................................................... 46 
Table 21. Summary of FAF Assessments at Baseline and Months 9 and 33 .............................................. 47 
Table 22. Summary of Total Areas of Decreased and Increased AF and Scaled Distance from Foveal 
Center as Assessed by FAF at Baseline and Months 9 and 33 .................................................... 49 
Table 23. Summary of CFP Assessments at Baseline and Months 9 and 33 .............................................. 52 
Table 24. Summary of Macular GA and CNV as Assessed by CFP at Baseline and Months 9 and 33 ..... 54 
Table 25. Summary of OCT Parameters Over Time ................................................................................... 56 
Table 26. Results of Physical Examination, Thyroid Palpation, Intracranial Hypertension, CNV and Optic 
Nerve Swelling Assessments Over Time .................................................................................... 57 
Table 27. Summary of Laboratory Assessments Over Time ...................................................................... 58 
Table 28. SAP-Specific Tables, Figures, and Listings (TFLs) to be Included in Primary Outcome Analysis 
Report .......................................................................................................................................... 62 
 


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TABLE OF LISTINGS 
Listing 1. Demographic Information by Participant ................................................................................... 58 
Listing 2. Rate of Change in Appropriately Transformed GA Area During Run-in and Treatment Phases 
as Determined Using FAF Images (Study Eye) .......................................................................... 59 
Listing 3. Rate of Change in Appropriately Transformed GA Area During Run-in and Treatment Phases 
as Determined Using CFP ........................................................................................................... 59 
Listing 4. Rate of Change in BCVA During Run-in and Treatment Phases ............................................... 60 
Listing 5. Rate of Change in LLVA During Run-in and Treatment Phases ............................................... 60 
Listing 6. Rate of Change in Central Retinal Thickness on OCT During Run-in and Treatment Phases ... 60 
 
TABLE OF FIGURES 
Figure 1. Consort Diagram of Participant Disposition ................................................................................ 61 
 


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VERSION HISTORY 
Version/Date 
Changes 
1.0/20DEC2018 
Initial Document  
2.0/20AUG2020 
Sections 3.1 and 3.3: Updated to specify that 45 participants will be enrolled; 
Section 4.3: Added per-protocol population 3; 
Section 4.6: Provided clarification on p-value thresholds for one-sided tests in addition 
to two-sided tests; 
Sections 5.0, 6.1, 6.2, 7.1, 7.1.2, 7.1.3: Indicated that information will be presented by 
site; 
Section 5.0: Updated to present participants who withdraw from IP separately, if 
sufficient data are present; 
Section 7.1: Updated per NIH Intramural Research Program Policy 801 and separated 
summaries for participant-specific and non-participant-specific protocol deviations; 
Sections 7.1.2 and 7.1.3: Removed waiver language previously included in protocol; 
Section 8.0: Removed redundant term in model for primary outcome analysis; 
Sections 9.1 and 11.0: Added analyses based on Student’s paired t-test for GA area 
expansion rates based on FAF as secondary and exploratory analyses, respectively; 
Section 10.0: Added sensitivity analysis based on per-protocol population 3; 
Section 12.1: Updated “E-ETDRS letters” to “letter score”; 
Section 13.4: Added thresholds for clinical significance for IOP of >10 mmHg change 
from baseline and >30 mmHg; 
Section 17.0: Made applicable corresponding updates described above to mock shells. 
3.0/04OCT2022 
Title page: Added ClinicalTrials.gov identifier and placeholder for PI’s signature 
Sections 2.0: Updated to specify that DIRRL will grade OCT images as well; 
Section 3.1: Updated to clarify that participants recruited at the beginning of the study 
may complete the study as early as Month 45 at the discretion of the investigator. 
Section 3.4.3: Updated to point to later sections that provide additional details. 
Section 4.3: Updated to further clarify/define the analysis populations. 
Section 10.0: Updated to further clarify/define the method for calculating the rate of 
missingness. 
Section 11.0: Updated to further clarify/define the exploratory analyses to be 
performed. 
Section 13.7: Added information regarding descriptive summary of graded OCT 
parameters; 
Section 17.0: Edited the summary of age as a continuous parameter from Table 2 to 
remove participants whose age is > 89 (ages > 89 are considered Protected Health 
Information (PHI) and are masked prior to transfer of data to the Coordinating Center); 
added Table 26 corresponding to graded OCT parameters; updated numbering of other 
relevant tables; updated formatting and footnotes of select tables for increased clarity 
Section 18.0: Added section to indicate the presentations to be included in the primary 
outcome analysis report. 
 
4.0/21MAR2023 
Section 3.4.2: Removed “changes in macular sensitivity on microperimetry” as a 
secondary study outcome as this was made an exploratory study outcome through 
Amendment M of the protocol. 
Section 9.6: Removed this section as macular sensitivity was made an exploratory 
study outcome. 
Section 17.0: Revised Table 14 to remove presentation of statistics pertaining to non-
qualifying fellow eyes. Removed Table 15 and Listing 7 as macular sensitivity was 
made an exploratory study outcome. Revised Table 1 and Figure 1 to more clearly 
depict participants who complete or discontinue the study at or after Month 45. 
  
 


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LIST OF ABBREVIATIONS
AE 
Adverse Event 
AF 
Autofluorescence  
AMD 
Age-Related Macular Degeneration 
AREDS 
Age-Related Eye Disease Study 
BCVA 
Best-Corrected Visual Acuity 
BEH 
Bristol Eye Hospital 
CFH 
Complement Factor H 
CFP 
Color Fundus Photos 
CI 
Confidence Interval 
CNV 
Choroidal Neovascularization 
COVID-19 
Coronavirus Disease 2019  
DDAF 
Definitely Decreased Autofluorescence 
DIRRL 
Doheny Image Reading & Research Lab 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EVA 
Electronic Visual Acuity 
FAF 
Fundus Autofluorescence 
GA 
Geographic Atrophy 
IAF 
Increased Autofluorescence  
IOP 
Intraocular Pressure 
IP 
Investigational Product 
LLVA 
Low Luminance Visual Acuity 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MCAR 
Missing Completely at Random 
MI 
Multiple Imputation 
MPS DA 
Macular Photocoagulation Study Disk Area 
NEI 
National Eye Institute 
OCT 
Optical Coherence Tomography 
PHI 
Protected Health Information 
PT 
Preferred Term 
QDAF 
Questionably Decreased Autofluorescence 
RPE 
Retinal Pigment Epithelial  
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SNP 
Single Nucleotide Polymorphism 
SOC 
System Organ Class 
Std Err 
Standard Error 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
YAG 
Yttrium Aluminum Garnet 


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1.0 
INTRODUCTION 
This statistical analysis plan provides proposed analyses for the study “Evaluation of Oral 
Minocycline in the Treatment of Geographic Atrophy Associated with Age-Related Macular 
Degeneration (GA).” This document contains 17 sections: (1) background of the study, (2) data 
sources for analyses, (3) an overview of the study design, (4) statistical considerations,  
(5) participant disposition, (6) participant characteristics, (7) participant compliance, (8) statistical 
analyses for primary outcome, (9) statistical analyses for secondary outcomes, (10) sensitivity 
analyses, (11) exploratory analyses, (12) review of ocular safety outcomes, (13) review of other 
safety outcomes, (14) rationale for any deviations from this statistical analysis plan, (15) quality 
assurance plans, (16) references and (17) proposed data tables, figures and listings. Any deviation 
from this statistical plan, not outlined in Section 14.0, will be described and justified in protocol 
amendments and/or in the final study report, as appropriate. 
1.1 
Age-related Macular Degeneration (AMD) 
AMD is the leading cause of late onset visual impairment and legal blindness in people 65 years 
of age or older in the United States (1, 2). The World Health Organization has placed AMD as the 
third leading cause of blindness worldwide. The phrase “age-related” is associated with macular 
degeneration because data show that the risk of developing AMD dramatically increases after age 
60. It is estimated that 13 million people in the United States, age 40 and older, have signs and 
symptoms of macular degeneration. Based on population demographics and current prevalence 
data, the number of individuals affected with AMD will double in the year 2020. 
AMD is a disease of the macula, the central area within the posterior retina that helps produce 
sharp, central vision. Central vision is required for seeing objects clearly and for common daily 
activities essential for independent living such as reading, writing, sewing and driving. While the 
pathogenesis of AMD remains unknown, several lines of evidence have indicated the role of 
inflammation. Complement factor H (CFH) is a major regulatory factor in the complement 
cascade. Several groups have identified single nucleotide polymorphisms (SNPs) in the CFH gene 
that are associated with AMD. A single copy of the risk-associated haplotype increases the risk of 
AMD by two- to four-fold, whereas those with a dual copy may increase their lifetime risk by  
five- to seven-fold (3-7). Macrophages are known to have an important role in the initiation and 


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maintenance of the immune response, including the regulation of complement activation.  
Previous studies have shown that patients with AMD were more likely to have circulating, 
activated macrophages (which produce high amounts of proinflammatory cytokines) compared to 
controls without AMD (8). 
1.2 
Treatment of Age-related Macular Degeneration 
Treatment of AMD has mostly focused on therapy for neovascular AMD. These have included 
classic laser photocoagulation, photodynamic therapy (verteporfin, Visudyne£) and anti-vascular 
endothelial growth factor (VEGF) pegylated aptamer (pegaptanib sodium, Macugen£), an  
anti-VEGF monoclonal antibodies ranibizumab (Lucentis£) and aflibercept. 
In October 2001, the results of the Age-Related Eye Disease Study (AREDS), a multi-center, 
randomized, controlled clinical trial of high-dose vitamins C and E, beta carotene and zinc 
supplements demonstrated a 25% reduction in the risk of progression to late AMD (9).  
However, this effect appears to be limited to reducing risk for progressing to neovascular AMD 
and does not influence the risk for progression to geographic atrophy (GA) (unpublished data). 
There are currently no available treatments or therapies for GA that have demonstrated efficacy in 
either preventing the onset, slowing the progression of disease, or improving vision of affected 
patients. 
1.3 
Geographic Atrophy 
Atrophic AMD or GA is characterized by an absence of neovascular changes and the gradual 
progression of atrophic changes in the macula on the level of outer retina and the retinal pigment 
epithelial (RPE) cell layer, resulting in progressive central vision loss. Over time, this progresses 
to result in serious impairment of central vision and often legal blindness. Wet or exudative AMD 
can also arise in the context of GA. Both GA involving the center of the macula and wet AMD are 
considered forms of late AMD. 
 
 


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One of the most common signs in early or intermediate AMD is drusen, which is typically seen in 
people over the age of 60. Drusen are usually seen clinically as whitish-yellow irregularities under 
the retina. Large drusen have been shown to contain immunoglobulins, activated microglia and 
fragments of activated complement factors (10-12), which may be a source of chronic 
inflammatory stimulus in the aging retina. In the absence of findings consistent with late AMD, 
intermediate AMD is typically defined as the presence of large (>125μm) macular drusen and/or 
pigmentary (hypopigmentary or hyperpigmentary) changes, while early AMD is typically defined 
as the presence of macular drusen <125μm in size. 
2.0 
DATA SOURCE 
All data analyzed will come from one of two sources. Data received from the National Eye Institute 
(NEI) will be collected via their electronic data capture system (EMR), which will then be 
uploaded on a daily basis to the Coordinating Center’s database, Advantage EDC. Data received 
from the Bristol Eye Hospital (BEH) and Doheny Image Reading and Research Lab (DIRRL) will 
be collected directly through Advantage EDC. 
It is expected that the data received from DIRRL will only contain data concerning the grading of 
participants’ Color Fundus and Fundus Autofluorescence (FAF) photos at all visits and Optical 
Coherence Tomography (OCT) images at baseline, Month 9 and Month 33, while the data received 
from NEI and BEH will contain all other participant data. 
3.0 
GENERAL REVIEW OF STUDY DESIGN 
3.1 
Study Design 
The GA study is a multi-center, prospective, single-arm, Phase II study to evaluate minocycline as 
a potential treatment to decrease the rate of worsening of GA associated with AMD. Up to  
45 participants will be enrolled and will undergo a nine month run-in phase prior to receiving 
investigational product (IP). During this run-in phase, participants will have a total of four  
pre-treatment visits at baseline and Months 3, 6 and 9. Following the run-in phase, beginning at 
Month 9, participants will receive an oral dose of 100 mg of minocycline twice daily for  
36 months and will return to the clinic at Months 12, 15, 21, 27, 33, 39, and 45 for follow-up 
assessments. The study is designed with a common termination date, meaning it will not terminate 


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until the last recruited participant has completed the Month 45 visit. Therefore, participants 
enrolled at the beginning of the study could receive additional months of IP beyond the scheduled 
36-months and will continue to be followed every six months until the common termination date. 
However, participants may complete participation in the study as early as Month 45, at the 
discretion of the investigator. Although participants may withdraw from IP during the study, all 
participants will be asked to return for all visits through their study termination visit. 
3.2 
Study Objective 
The study objective is to investigate the safety and possible efficacy of oral minocycline for 
slowing down the worsening of GA associated with AMD. 
3.3 
Study Population 
Up to forty five (45) participants, aged 55 years or older, with unilateral or bilateral GA associated 
with atrophic AMD will be enrolled in this study. Approximately 20-25 participants will be 
enrolled at NEI, and approximately 20-25 participants will be enrolled at BEH to reach the target 
sample size of 45 participants. Participants who withdraw or are lost to follow-up before the Month 
33 visit (i.e., before completing 24 months on treatment) may be replaced by new enrollments up 
to 30 participants at NEI and 30 participants at BEH. 
3.3.1 Participant Eligibility Criteria  
To be eligible, participants must meet all of the inclusion criteria, when applicable, and none of 
the exclusion criteria. 
3.3.1.1 
Inclusion Criteria 
1. Participant must be 55 years of age or older. 
2. Participant (or legal guardian) must understand and sign the protocol’s informed consent 
document. 
3. Participant must have evidence of early or intermediate AMD as defined by characteristic 
presence of drusen and/or pigmentary changes. 
4. Participant must be able to swallow capsules. 


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5. Participant must have normal renal function and liver function or have mild abnormalities 
not above grade 1 as defined by the Common Terminology Criteria for Adverse Events 
v4.0. 
6. Participant must agree to minimize exposure to sunlight or artificial ultraviolet rays and to 
wear protective clothing, sunglasses and sunscreen (minimum sun protection factor of 15) 
when out in the sun. 
7. Any female participant of childbearing potential must have a negative pregnancy test at 
screening and be willing to undergo pregnancy tests throughout the study. 
8. Any female participant of childbearing potential and any male 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 two acceptable methods of 
contraception throughout the course of the study and for at least one week after IP 
discontinuation. 
3.3.1.2 
Exclusion Criteria 
1. Participant is actively receiving study therapy in another investigational study. 
2. Any female participant of childbearing potential who is pregnant, breast-feeding or 
planning to become pregnant during the study. 
3. Participant is expected to be unable to comply with study procedures or follow-up visits. 
4. Participant is on ocular or systemic medications known to be toxic to the lens, retina or 
optic nerve (e.g., ethambutol, chloroquine, or hydroxychloroquine). 
5. Participant has a condition that would preclude participation in the study (e.g., unstable 
medical status including blood pressure and glycemic control) by interfering with the 
participant’s ability to engage in the required protocol evaluation and testing and/or comply 
with study visits. 
6. Participant has a history of chronic renal failure requiring dialysis or kidney transplant. 
7. Participant has a history of chronic hepatitis or liver failure. 
8. Participant has a history of thyroid cancer. 


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9. Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline 
family. 
10. Participant is currently taking minocycline or another tetracycline medication. 
11. Participant is taking any medication that could adversely interact with minocycline such as 
methoxyflurane. 
12. Participant has a prior history of idiopathic intracranial hypertension. 
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 study eye must have greater than ½ disc area (approximately 1 mm2) of GA compatible 
with dry AMD. GA is defined as one or more well-defined and often circular patches of 
partial or complete depigmentation of the RPE, typically with exposure of underlying 
choroidal blood vessels. Even if much of the RPE appears to be preserved and large 
choroidal vessels are not visible, a round patch of RPE partial depigmentation may be 
classified as early GA. The GA in the study eye must be able to be photographed in their 
entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can 
complicate area measurements. 
2. The total area of GA lesions combined should be less than 7.0 MPS disc areas (DA) (17.78 
mm2) as evident on FAF imaging. 
3. The visual acuity of the study eye should be >19 E-ETDRS letters (i.e., 20/400 or better).  
4. The study eye must have clarity of ocular media and degree of pupil dilation sufficient to 
permit adequate fundus photographs. 


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3.3.2.2 
Study Eye Exclusion Criteria 
1. Current evidence of choroidal neovascularization (CNV) as determined by the treating 
physician or a history of treatments for CNV. 
2. Evidence of retinal atrophy due to causes other than atrophic AMD. 
3. Current evidence or history of ocular disorders in the study eye that in the opinion of the 
investigator confounds study outcome measures, including (but not limited to): 
a. Non-proliferative diabetic retinopathy involving 10 or more hemorrhages or 
microaneurysms, or active proliferative diabetic retinopathy 
b. Branch or central retinal vein or artery occlusion 
c. Macular hole 
d. Pathologic myopia  
e. Uveitis 
f. Pseudovitelliform maculopathy 
4. History of vitreoretinal surgery. 
5. Need for ocular surgery during the course of the study. 
6. Recent history of lens removal (< 3 months) or Yttrium Aluminum Garnet (YAG) laser 
capsulotomy (< 1 month). 
3.3.2.3 
Choice of Study Eye in Cases of Bilateral Disease 
If both eyes meet the study eye eligibility criteria described above, the eye with the better 
best-corrected visual acuity (BCVA) will be chosen as the study eye. If both eyes are of equal 
visual acuity (VA), the study eye will be assigned by the enrolling investigator. For participants 
with two qualifying eyes, the fellow (non-study) eye will be noted as a “qualifying fellow eye” 
and anatomical data from it will be analyzed as part of the secondary outcome measures. 


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3.4 
Outcomes 
3.4.1 Primary Study Outcome 
The primary outcome is the difference in the rates of GA area expansion in the study eye between 
the run-in phase of the study and following IP initiation. GA area determination will be based on 
digital grading of FAF images by an external Reading Center. Specifically, the primary outcome 
will be the difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months 
of treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9). 
3.4.2 Secondary Study Outcomes 
Exploratory secondary outcomes will examine the difference in the rates of outcome measure 
progression in the study eye between the run-in phase of the study and following IP initiation. 
Measures obtained from qualifying fellow eyes will also be analyzed separately and together with 
study eyes as secondary outcomes. 
Specifically, the secondary outcome measures include difference in rates of progression from IP 
start visit (Month 9) to 24 months of treatment (Month 33) compared to initial study visit  
(Month 0) to IP start visit (Month 9) in (a) study eyes alone, (b) qualifying fellow eyes alone and 
(c) study and qualifying fellow eyes together in the following: 
1. GA area expansion based on FAF images by an external Reading Center using a different 
statistical approach compared to primary outcome 
2. GA area expansion based on digital grading of color fundus images by an external Reading 
Center 
3. changes in BCVA 
4. changes in low luminance visual acuity (LLVA) 
5. changes in central retinal thickness on OCT and 


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3.4.3 Safety Outcomes 
Ocular safety outcomes include: 
1. Changes in VA 
2. Ocular surface changes 
3. Intraocular inflammation and 
4. Any other ocular changes not consistent with the natural progression of GA 
Additional details regarding ocular safety outcomes are provided in Section 12.1 and Section 12.2. 
Other safety outcomes include: 
x Frequency, type, severity and assessed relatedness to IP of Adverse Events (AEs) 
x Number of participants withdrawn from IP due to vision loss, AEs and treatment failures 
4.0 
STATISTICAL CONSIDERATIONS 
4.1 
Sample Size Calculation  
The accrual goal is to enroll 45 participants, approximately 20 at NEI and 25 at BEH.  
Up to 15 additional participants may be enrolled to replace those participants who withdraw prior 
to their Month 33 visit. This sample size was determined for the primary analysis of the difference 
in rate of change in square-root transformed GA area in the study eye between IP start visit to  
24 months of treatment and initial study visit to IP start visit. A two-sided paired t-test at an alpha 
level of 0.05, comparing square-root transformed rates of change in GA between 24 months of 
treatment and the run-in phase was employed. 
A rate of 1.52 mm2/year is assumed for the run-in phase in the current study, based on the median 
GA expansion rates suggested in the literature (13). For data that are skewed, the square-root of 
the mean is not equal to the mean of the square-root transformed data. However, since a quantile 
of strictly positive data is invariant to transformation (e.g., the square-root of a given quantile of 
the original observations is equal to that quantile of the transformed observations), and for 
symmetric data mean and median are equal, the square-root of the median progression rate  
¥PP2/year = 1.23 mm/year) is used to approximate the assumed mean progression rate for 


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the square-root transformed run-in phase. The treatment phase is assumed to have a 25% reduction 
in the GA growth rate, equivalent to a 13% reduction of the square-root transformed rate, implying 
a mean progression rate of 1.07 mm/year for the square-root transformed GA growth rate during 
the treatment phase. A standard deviation of 0.30 mm/year was obtained from previous NEI GA 
protocols exploratory analyses data and was assumed for the GA growth rate during the run-in 
phase. Given the strictly positive nature of GA enlargement, a reduction in mean progression rate 
during the treatment phase necessitates a smaller standard deviation. However, on the square-root 
scale, the difference in standard deviations between the run-in and treatment phases is negligible 
for the proposed 25% reduction in means, and a standard deviation of 0.30 was also assumed for 
the square-root transformed GA growth rate during the treatment phase. Since this is a single arm 
study utilizing each participant as their own control, measurements will be highly correlated 
between the run-in and treatment phases. A correlation of 0.8 was used to account for the high 
dependence in measurements between the run-in and treatment phases. Based on these square-root 
transformed mean and standard deviation estimates, a sample size of at least 17 participants is 
required to obtain at least 90% power to detect a difference in progression rates if the true  
square-root transformed progression rates are 1.23 mm/year during the run-in phase and 1.07 
mm/year during the treatment phase of 24 months, with an 80% within-in participant correlation. 
Since the study population consists of older adults, loss to follow-up due to various reasons is 
expected and needs to be taken into account for an accurate sample size. Therfore, the target sample 
size for this study is 45 participants, with a provision to enroll up to an additional 15 participants 
to replace those participants who withdraw prior to their Month 33 visit. Approximately 12 months 
will be necessary to accrue these participants. 
Sunness, et al. (14), (13) state that a sample size of 306 is necessary to detect a treatment effect of 
25% when examining the effect of a new systemic treatment on GA growth rate in individuals 
(14). One of the factors that resulted in the reduction of sample size from the Sunness suggestion 
is the use of FAF instead of color fundus photos (CFP) to grade GA. FAF appears to be more 
precise (i.e., lower within-patient SD) than CFP. For example, the coefficient of variation for 
the square-root transformed FAF data is 2.5, while the coefficient of variation for the CFP data 
summarized in Sunness is 1.3. Further, the current study design utilizes each participant as their 
own control, significantly decreasing within-participant variability and the need for a large sample 
size. 


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4.2 
Sample Size Re-estimation 
After the first 15 participants have reached their Month 9 visit, the study dropout rate will be 
assessed and a sample size re-estimation may be performed to ensure at least 17 participants 
complete Month 33 visit. 
The current drop-out rate will be determined as: 
Number of participants who withdraw from the study 
Number of participants enrolled in the study 
 
Sample size will be re-estimated as follows: 
Minimum number of participants required 
1-Current drop-out rate 
If the re-estimated sample size is more than 60 participants (planned target sample size of 45 + 
provision to enroll 15 additional participants to replace those participants who withdraw prior to 
their Month 33 visit), then the sample size may be revised to accommodate the increased  
drop-out rate observed after discussion between the Principal Investigator and Coordinating 
Center. 
4.3 
Analysis Populations 
The following analysis populations will be considered for this study: 
Enrolled population: Includes all participants enrolled in the study, regardless of compliance, 
follow-up or treatment received. Participant disposition, characteristics, compliance, primary 
outcome analysis, and summaries of pre-treatment AEs will be based on this population. 
Safety population: Includes all participants who received at least one dose of the study drug. 
Summaries of ocular and other safety outcomes will be based on this population. 
Per-protocol population 1: Includes those participants who completed treatment through Month 33 
without any missing observations for the assessment and eye(s) being summarized. Sensitivity 
analysis will be performed using this population. 


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Per-protocol population 2: Includes those participants who completed at least three follow-up visits 
during the treatment phase and did not discontinue treatment prior to the completion of at least 
three follow-up visits. For participants included in this population, all visits subsequent to 
treatment discontinuation will be excluded from analyses. Summaries of secondary outcomes will 
be based on this population. Sensitivity analysis will also be performed using this population. 
Per-protocol population 3: Includes all participants in the enrolled population except those who 
initiated treatment during the Month 9 visit out of window. Sensitivity analysis will be performed 
using this population. 
4.4 
Study Phases 
The study is divided into two phases: 
1. Run-in phase: Defined as the time from Baseline through Month 9 before participants 
receive the first dose of IP. 
2. Treatment Phase: Defined as the time from Month 9 after participants receive the first dose 
of IP through early withdrawal from study or study completion. Participants who received 
at least one dose of IP but withdrew from IP early, will be considered to be in the treatment 
phase until withdrawal from or completion of study. Therefore, all participants who are 
followed during the treatment phase, regardless of whether they discontinued IP, will be 
included in the corresponding analysis, unless otherwise specified.  
4.5 
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. 
4.6 
Statistical Tests and Adjustments for Multiple Comparisons 
Results of statistical analyses are considered significant if the p-value from the statistical test is  
< 0.05 for two-sided tests or <0.025 for one-sided tests. Results will be considered moderately 
significant if the p-value from the statistical test is < 0.10 for two-sided tests or <0.05 for one-sided 
tests. 


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Since all analyses in this study are considered exploratory, no adjustments for multiple 
comparisons will be made. 
4.7 
Handling Duplicate Assessments 
The assessments at each visit may be completed over multiple days. If assessments are performed 
more than once at a given visit, the results of the most recent assessment will be considered in the 
analysis. For example, if the Month 3 visit is completed over multiple days and an assessment was 
performed on more than one day as part of Month 3 assessment, then the results of the most recent 
Month 3 visit will be included in the analyses. 
4.8 
Software for Analyses 
Statistical analyses will be performed using SAS version 9.4 or higher or R v3.3.1 or higher.  
All tables, listings and figures presented in the analysis will be created using either SAS v9.4 or 
Rv3.3.1 or higher.  
5.0 
PARTICIPANT DISPOSITION 
Overall participant disposition including the number and percentage of participants enrolled, 
completed the run-in phase, initiated and completed the treatment phase, and discontinued study 
early will be summarized by site. Reasons for study discontinuation will also be summarized 
(Table 1). If sufficient data are present, reasons for treatment discontinuation will be summarized. 
The number and percentage of participants who withdraw from IP due to safety, including due to 
vision loss in a manner inconsistent with the natural history of GA (manually identified based on 
investigator’s comments for those particpiants with reason for withdrawal from IP indicated as 
“safety withdrawal”) and AEs (reason for withdrawal from IP indicated as “safety withdrawal” for 
the occurrence of AEs assessed as being related to study IP that preclude further administration of 
IP), and treatment failure (reason for withdrawal from IP indicated as “lack of efficacy”) will be 
included. These tables will be based on the enrolled population. 
Participant flow as outlined in Figure 1 will also be presented. 


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6.0 
PARTICIPANT CHARACTERISTICS 
These presentations will be based on the enrolled population. 
6.1 
Participant Demographics 
Demographic characteristics including baseline age, sex, race and ethnicity will be summarized by 
site as outlined in Table 2 and listed as in Listing 1. The listing will also include the registration 
date and will indicate the eye determined to be the study eye and whether the participants’ fellow 
eye is a qualifying fellow eye. 
6.2 
Medical and Ocular History 
The total number and percentage of participants with a history of medical and ocular conditions 
and ocular procedures will be summarized. History of ocular conditions and procedures will also 
be summarized by eye (study eye, qualifying fellow eye and non-qualifying fellow eye) (Table 3). 
Separate summaries will be included for each site. Medical and ocular history will also be listed; 
the listing will include date of diagnosis and/or time since diagnosis at baseline for select 
conditions and procedures. 
7.0 
PARTICIPANT COMPLIANCE  
These presentations will be based on the enrolled population. 
7.1 
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 site 
and overall.  
Effective July 1, 2019, with the implementation of 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. Separate summaries will 
be included for participant-specific and non-participant specific protocol deviations (Table 4 and 
Table 5, respectively). Listings of participant-specific and non-participant-specific protocol 
deviations and unanticipated problems will be presented. 


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7.1.1 IP Compliance Deviations 
This table will present the expected number of doses, number of doses missed and compliance 
rates cumulatively and between visits for each participant (Table 6). For each participant, the 
number of expected doses overall and between visits will be calculated as follows: 
N Doses expected (cumulative) = (Date Early IP/study withdrawal or study completion — Date IP first taken)*2 
N Doses expected (between visits) = (Date Current visit — Date Previous visit IP start)*2 
If participants took IP on the date they withdrew from the study or completed the study, the number 
of expected doses overall and between the last visit and the previous visit will be calculated as 
follows: 
N Doses expected (cumulative) = (Date Early IP/study withdrawal or study completion — Date IP first taken + 1)*2 
N Doses expected (between visits) = (Date Current visit — Date Previous visit IP start + 1)*2 
Date IP first taken is the date participant first started taking the pills. If this date is missing, then the 
date of the visit when IP was first dispensed (i.e, Month 9 visit) to the participant will be used; 
however, if the IP was mailed to the participant instead, then the date when the mail was sent will 
be used. Similarly, Date Previous visit IP start is the date participant started taking the pills following the 
previous visit. If this date is missing, then the date of the previous visit when IP was dispensed to 
the participant will be used; however, if the IP was mailed to the participant instead, then the date 
when the mail was sent will be used. 
The sites will report number of pills returned at each study visit. Number of doses taken and missed 
will be calculated for each participant for each timeframe as: 
N Doses taken = N Pills dispensed — N Pills returned 
N Doses missed = N Doses expected — N Doses taken 
Negative values will indicate participants who took excess IP. 


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Compliance rate for each timeframe will be calculated as: 
Compliance rate = (N Doses taken/N Doses expected)*100 
Participants with compliance rates between visits less than 50% will be flagged in this table. 
7.1.2 Study Procedure Deviations 
This table will present the number of procedures not completed, the expected number of 
procedures completed, and the percentage of procedures missed a) for each participant considering 
all procedures together, b) cumulatively for all participants by procedure and c) cumulatively for 
all participants considering all procedures (Table 7). Statistics will be presented for each site and 
overall. Number of procedures not completed is defined when the site reports a missed procedure 
or when the protocol monitors note missed procedures at a site, and will be presented as a sum. 
Expected number of procedures is defined based on the study flowsheet included in the protocol, 
and will also be presented as a sum. Percentage of procedures missed will be calculated as follows: 
(N procedures not completed / N expected procedures completed)*100 
7.1.3 Visit Schedule Deviations 
This table will present the number of expected visits, number of missed study visits, the percentage 
of missed study visits, the number of out of window visits, and the percentage of out of window 
visits cumulatively and by participant (Table 8). Statistics will be presented for each site and 
overall. Number of expected, missed and out of window study visits will be calculated from the 
study flowsheet and will all be presented as sums. The percentage of missed study visits will be 
calculated as: 
(N visits missed / N expected visits)*100 
Similarily, the percentage of out of window study visits will be calculated as: 
(N visits out of window / N expected visits)*100 
 


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7.2 
Premature Treatment and Study Withdrawals 
Participants who withdrew from treatment and study early will be summarized as outlined in 
Section 5.0 and will be listed separately along with reason(s) for withdrawal. Participants who 
discontinue IP early due to vision loss in a manner inconsistent with the natural history of GA, 
AEs and treatment failure will be included in the listing (see Section 5.0 for identification of such 
participants). 
8.0 
PRIMARY OUTCOMES ANALYSIS 
GA area, based on digital grading of FAF imaging, will be assessed at all study visits in study and 
qualifying fellow eyes. 
The difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of 
treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9), as 
determined using FAF, in study eyes will be assessed by fitting a linear spline regression model 
with a fixed knot at Month 9. 
The model will be fit using the MIXED procedure in SAS 9.4 or higher using GA area as the 
outcome that’s appropriately transformed to satisfy the linear trend assumption as follows: 
Model 1: Yt = ȕ0 + ȕ1*Timet + + ȕ2*(Timet – t*) + bt + İt 
Where: 
<W = Estimate of mean of appropriately transformed GA area at Month t 
t = Time in months from baseline 
t* = Month when treatment started or month corresponding to the knot (i.e.,Month 9) 
ȕ0 = Estimate of mean of appropriately transformed GA area at baseline 
ȕ1 = Estimate of rate of change in appropriately transformed GA area during the run-in phase 
ȕ2 = Estimate of difference in rates of change in mean of appropriately transformed GA area 
between the treatment phase and run-in phase LHȕ2 is applicable only to time points after the 
knot [Month 9]) 


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bt =Within-subject correlation 
İt = Random variability not explained by the model at Month t, which is assumed to be normally 
distributed and independent across participants and time. 
Note that ȕ1 + ȕ2 = Estimate of rate of change in appropriately transformed GA area during the 
treatment phase 
Square-root transformation of the GA area will be used in the model. If the square-root 
transformation does not achieve a sufficiently symmetric distribution, Box-Cox or logarithm 
transformations may be used. 
The analysis will only include measurements from study eyes, will treat missing observations as 
missing completely at random (MCAR) and will be based on the enrolled population as outlined 
in Table 9. Table 9 also includes information described in Sections 10.0 and 11.0. Information will 
also be presented by participant (Listing 2). 
,IWKHHVWLPDWHRIȕ2 is < 0 and the corresponding p-value is < 0.025, then the treatment is indicated 
to have slowed the rate of progression of GA 
9.0 
SECONDARY OUTCOMES ANALYSIS 
The analysis of secondary outcomes will be considered exploratory in nature and will be based on 
per-protocol population 2, unless otherwise specified. 
9.1 
Area of GA based on Fundus Autofluorescence (FAF) 
The difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of 
treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9), as 
determined using FAF, will be assessed using Student’s paired t-test for: 
1. Study eyes alone 
2. Qualifying fellow eyes alone 
3. Study eyes and qualifying fellow eyes together 


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as shown in Table 10. This analysis will use appropriately transformed GA area, the enrolled 
population, and treat missing observations as MCAR. Rate of appropriately transformed GA area 
expansion will be calculated as follows for each participant: 
Rate of appropriately transformed GA area expansion during run-in phase (mm/year) = 
(Appropriately transformed GA AreaMonth 9 – Appropriately transformed GA AreaBaseline)/((Date 
Month 9 – DateBaseline)/365.25) 
Rate of appropriately transformed GA area expansion during treatment phase (mm/year) = 
(Appropriately transformed GA AreaMonth 33 – Appropriately transformed GA AreaMonth 9)/((Date 
Month 33 – DateMonth 9)/365.25) 
The following hypotheses will be evaluated using the TTEST SAS procedure: 
H0ǻRun-in phase  ǻTreatment phase 
HAǻRun-in phase ǻTreatment phase 
Where: 
ǻRun-in phase = Mean rate of appropriately transformed GA area expansion during the run-in phase 
ǻTreatment phase = Mean rate of appropriately transformed GA area expansion during the treatment 
phase. 
9.2 
Area of GA based on Color Fundus Photos (CFP) 
GA area, based on CFP, will be assessed at all study visits in study and qualifying fellow eyes. 
The difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of 
treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9), as 
determined using CFP, will be assessed by fitting a linear spline regression model with a fixed 
knot at Month 9, similar to Model 1, in study eyes alone, qualifying fellow eyes alone and study 
and qualifying fellow eyes together (Table 11, Listing 3). Table 11 also includes information as 
outlined in Section 11.0). The outcome of the model will be GA area, that’s appropriately 
transformed to satisfy the linear trend assumption. The analysis will treat missing observations as 
missing completely at random (MCAR). 


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9.3 
Best-Corrected Visual Acuity (BCVA) 
Visual acuity measures for each eye will be obtained using an electronic visual acuity (EVA) 
algorithm. 
Mean rate of change in BCVA during the treatment phase will be compared to the mean rate of 
change in BCVA during the run-in phase using Student’s paired t-test for 
1. Study eyes alone 
2. Qualifying fellow eyes alone 
3. Study eyes and qualifying fellow eyes together 
as shown in Table 12. Rate of change in BCVA during run-in and treatment phases as well as 
change in these rates between the phases will be presented as in Listing 4. Rate of change in BCVA 
will be calculated as follows for each participant: 
Rate of change in BCVA during run-in phase (BCVA letters/month) = (BCVA letter scoreMonth 9 – 
BCVA letter scoreBaseline)/((Date Month 9 – DateBaseline)/30.4) 
Rate of change in BCVA during treatment phase (BCVA letters/month) = (BCVA letter scoreMonth 
33 – BCVA letter scoreMonth 9)/((Date Month 33 – DateMonth 9)/30.4) 
Mean rate of change during the treatment phase will be assessed at Month 33 compared to  
Month 9. The following hypotheses will be evaluated using the TTEST SAS procedure: 
H0ǻRun-in phase  ǻTreatment phase 
HAǻRun-in phase ǻTreatment phase 
Where: 
ǻRun-in phase = Mean rate of change in BCVA during the run-in phase 
ǻTreatment phase = Mean rate of change in BCVA during the treatment phase. 
9.4 
Low Luminance Visual Acuity (LLVA) 
LLVA will be evaluated in a similar manner as BCVA (Table 13, Listing 5). 


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9.5 
Central Retinal Thickness 
Central retinal thickness, as measured on OCT, will be evaluated in a similar manner as BCVA 
(Table 14, Listing 6). 
10.0 
SENSITIVITY ANALYSES 
Sensitivity analysis will be performed by assessing the difference in the rate of GA area expansion 
from IP start visit (Month 9) to 24 months of treatment (Month 33) compared to initial study visit 
(Month 0) to IP start visit (Month 9), as determined using FAF, in study eyes by fitting a linear 
spline regression model with a fixed knot at Month 9, similar to Model 1, as follows: 
1. Using enrolled population and multiple imputation (MI) for missing observations if >10% 
of the overall observations for the assessment and eye(s) being analyzed are missing. 
Observations are considered missing if for a given assessment and eye at a given visit, the 
participant has not previously terminated from the study, the visit is not missing, and the 
data for the given assessment and eye are not available. The rate of missingness, for all 
subjects (i=1, … n) will be calculated for a given outcome as follows: 
σ
# ݉݅ݏݏ݅݊݃ ݋ܾݏ݁ݎݒܽݐ݅݋݊ݏ௜
௡
௜ୀଵ
σ
# ݒ݅ݏ݅ݐݏ ݌ݎ݅݋ݎ ݐ݋ ݏݐݑ݀ݕ ܿ݋݉݌݈݁ݐ݅݋݊/݁ܽݎ݈ݕ ݐ݁ݎ݉݅݊ܽݐ݅݋݊௜כ # ݁ݕ݁ݏ ௜
௡
௜ୀଵ
כ 100 
Under the assumption that the transformation of the rates of change in GA area are 
normally distributed, the missing rates from the run-in and treatment phases will be 
predicted from each participant’s observed area of GA and scheduled visits and joint 
relationships with other variables (e.g., participant’s age, visual acuities, OCT 
measurements, etc.); 
2. Using per-protocol population 1; 
3. Using per-protocol population 2 and treating missing observations as MCAR; 
4. Using per-protocol population 3 and treating missing observations as MCAR; 
as outlined in Table 9 (note: Table 9 also includes information as described in Sections 8.0 and 11.0). 
11.0 
EXPLORATORY ANALYSES 
Exploratory analyses supplement the primary and secondary outcome analyses. 


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The difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of 
treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9), as 
determined using FAF, will be assessed by fitting a linear spline regression model with a fixed 
knot at Month 9, similar to Model 1, in: 
1) qualifying fellow eyes alone and/or 
2) study and qualifying fellow eyes together 
as outlined in Table 9.  
Further, the analysis may be repeated by determining the rate of change in appropriately 
transformed GA area during the treatment phase at other time points relative to Month 9 in study 
eyes alone, qualifying fellow eyes alone, and study and qualifying fellow eyes together.  
The association of IP compliance and drop-outs with treatment effect at Months 12, 15 and 21 may 
also be evaluated by adding IP compliance rates and/or drop-out rates to the model. Any lag in 
treatment effect may be assesed by adding another knot to the model. If there is sufficient data, the 
effect of rate of change in appropriately transformed GA area during the run-in phase on treatment 
response (i.e., rate of change in appropriately transformed GA area during the treatment phase) 
may be assessed. Further, appropriately transformed GA area will be plotted against time. 
The difference in the rate of GA area expansion from IP start visit (Month 9) to 24 months of 
treatment (Month 33) compared to initial study visit (Month 0) to IP start visit (Month 9), as 
determined using FAF, will also be assessed using Student’s paired t-test for study eyes alone, 
qualifying fellow eyes alone and/or study and qualifying fellow eyes together: 
1) Using enrolled population and MI for missing observations if >10% of the observations 
are missing, similar to sensitivity analysis described in Section 10.0 above; 
2) Using per-protocol population 1; 
3) Using per-protocol population 2 and treating missing observations as MCAR; 
as outlined in Table 10.The difference in the rate of GA area expansion from IP start visit (Month 
9) to 24 months of treatment (Month 33) compared to initial study visit (Month 0) to IP start visit 
(Month 9), as determined using CFP, may be assessed by fitting a linear spline regression model 
with a fixed knot at Month 9, similar to Model 1, for (a) study eyes alone, qualifying fellow eyes 


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alone, and study and qualifying fellow eyes together, (b) enrolled population, per-protocol 
population 1 and/or per-protocol population 2, and/or (c) treating missing observerations as MCAR 
and/or using MI (Table 11). 
Mean change in BCVA during the treatment phase may be compared to the mean change in BCVA 
during the run-in phase using Student’s paired t-test for non-qualifying fellow eyes. A similar 
anlaysis may be performed for central retinal thickness. Further, mean change in BCVA during 
the treatment phase at time points other than Month 33 relative to Month 9 may be compared to 
the mean change in BCVA during the run-in phase using Student’s paired t-test for study eyes 
alone, qualifying fellow eyes alone, study and qualifying fellow eyes together, and/or  
non-qualifying fellow eyes alone. A similar analysis may be performed for LLVA (except in  
non-qualifying fellow eyes) and central retinal thickness (except in non-qualifying fellow eyes) 
(Table 12 through Table 14). 
The number of participants with a 3-line (15-letter) worsening in BCVA during the treatment phase 
will be compared with the number of participants with a worsening during the run-in phase using 
a Chi-square test. If any of the expected cell counts is < 5, then Fisher’s exact test will be used 
(Table 12). 
Other exploratory analyses may be performed as appropriate. 
12.0 
OCULAR SAFETY OUTCOMES 
These presentations will be based on the safety population. All relevant information will be listed; 
data for all enrolled participants will be included in the listings. Outcome measurements or relevant 
change in outcome measurements may be plotted against time. 
12.1 
Best-Corrected Visual Acuity (BCVA) 
Visual acuity 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 eye (study eye, qualifying fellow eye, study eye and qualifying fellow eyes together,  
non-qualifying fellow eye) (Table 15). 


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Change from baseline of 15 letter score or more is considered clinically significant and participants 
experiencing a loss of >30 letter score from baseline may be withdrawn from the study at 
investigator’s discretion. Therefore, frequency and percentage of participants with change from 
baseline of >=15 letter score and loss of >30 letter score at each follow-up visit from baseline will 
be summarized. 
12.2 
Ocular Surface Changes and Inflammation 
Participants are monitored for ocular surface changes and inflammation starting at Month 9 in both 
eyes. Ocular surface changes are defined as any changes to the ocular surface that are clinically 
apparent on slit lamp examination and/or newly symptomatic, i.e., representing a change from IP 
initiation at Month 9 that is clinically meaningful in the judgment of the investigator. For example, 
this could include a clinically meaningful new finding of, or worsening in, punctate keratopathy, 
infectious or inflammatory keratitis, or corneal scarring. Intraocular inflammation could include 
the presence of clinically meaningful anterior chamber inflammatory activity (haze, cells, and/or 
keratic precipitates), vitreous activity (haze and/or cells), and/or signs of posterior uveitis or retinal 
vasculitis. The number and percentage of participants with ocular surface changes and 
inflammation at each visit will be summarized by eye (study eye, qualifying fellow eye, study eye 
and qualifying fellow eyes together, non-qualifying fellow eye) (Table 16). 
13.0 
OTHER SAFETY OUTCOMES 
These presentations will be based on the safety population, unless otherwise specified. All relevant 
information will be listed; data for all enrolled participants will be included in the listings.  
Outcome measurements or relevant change in outcome measurements may be plotted against time. 
13.1 
Adverse Events (AEs) 
All treatment-emergent AEs reported will be summarized. Treatment-emergent AEs are those 
events occuring at the time of or after administration of first dose of study drug. Total number and 
percentage of participants with AEs and number of AEs will be summarized by severity of the AE, 
ocular specification (ocular vs. systemic) and relatedness to the IP (Table 17). AEs will also be 
summarized by system organ class (SOC) and preferred term (PT) (Table 18). 


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If sufficient data are present, summaries similar to Table 17 and Table 18 will be generated for all 
serious adverse events (SAEs) and pre-treatment AEs (i.e, AEs occuring during run-in phase), and 
summaries similar to Table 18 will be presented for natual progressions of the disease.  
Summaries of pre-treatment AEs will be based on the enrolled population. 
All AEs, treatment-emergent or otherwise, will be listed. 
13.2 
Withdrawal from IP Due to Vision Loss, Adverse Events, and Treatment Failure 
Participants who discontinue IP due to vision loss, AEs and treatment failure will be summarized 
in Table 1 and will be listed as outlined in Section 7.2 (see Section 5.0 for identification of such 
participants). 
13.3 
Low-Luminance Visual Acuity (LLVA) 
LLVA is assessed at baseline and all follow-up visits except Months 6 and 12. The assessment 
will be performed only on study and qualifying fellow eyes. However, at investigator’s discretion, 
the assessment may also be performed on the non-qualifying fellow eye. 
Total letters read at each visit and change from baseline at each follow-up visit will be presented 
by eye (study eye, qualifying fellow eye, and study eye and qualifying fellow eyes together)  
(Table 19). Assessments performed on the non-qualifying fellow eyes will be included in listings. 
13.4 
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 summarized by eye (study eye, qualifying 
fellow eye, study eye and qualifying fellow eyes together, and non-qualifying fellow eye)  
(Table 20). Number of participants with IOP > 30 mmHg or change from baseline in IOP of > 10 
mmHg will be included in the summary in Table 20 and the individual occurrences will be 
highlighted in the listing. 
13.5 
FAF Assessments 
FAF image data are collected at all study visits in both eyes. The number and percentage of 
participants with decreased and increased autofluorescence (AF), various locations of definite 
decreased AF (DDAF), various junctional AF patterns (along with subcategories of diffused 


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junctional AF pattern) and significant medical findings at baseline and Months 9 and 33 will be 
summarized (Table 21). Participants whose images were obtained but could not be graded will be 
included in the denominators; participants for whom the assessment is not applicable or not 
evaluated will be excluded in the denominators. 
In addition, total areas of definite, questionable, and definite + questionable decreased and 
increased AF as well as distance from foveal center to the nearest point on the retina not showing 
DDAF, questionably decreased autofluorescence (QDAF) or increased autofluorescence (IAF) at 
baseline and Months 9 and 33 will be summarized. Change from baseline at Month 9 and change 
from Month 9 at Month 33 will be included. If correction factor was used, then scaled 
measurements will be used in the table (Table 22). 
Summaries may be presented for other visits as well. 
13.6 
CFP Assessments 
CFP data are collected at all study visits in both eyes. The number and percentage of participants 
with macular GA, evidence of CNV and other features such as RPE hyperplasia/pigmentation and 
RPE depigmentation will be summarized at baseline and Months 9 and 33 (Table 23).  
Participants whose images were obtained but could not be graded will be included in the 
denominators; participants for whom the assessment is not applicable or not evaluated will be 
excluded from the denominators. 
In addition, location of macular GA, total area of macular GA and distance from foveal center to 
nearest uninvolved retina at baseline and Months 9 and 33 will be summarized. Change from 
baseline at Month 9 and change from Month 9 at Month 33 will be included for total area of 
macular GA and distance from foveal center to nearest uninvolved retina. If correction factor was 
used, then scaled measurements will be used in the table (Table 24). 
Summaries may be presented for other visits as well. 
13.7 
OCT Assessments 
OCT data are collected at all study visits in both eyes, however, graded results from an external 
Reading Center are available only for baseline, Month 9 and Month 33. Central retinal thickness 
and linear GA enlargement on horizontal and vertical scans as measured on OCT at baseline, 


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Month 9 and Month 33 will be summarized. Change from baseline at Month 9 and change from 
Month 9 at Month 33 will be included (Table 25). 
13.8 
Physical Examination, Thyroid Palpation, Intracranial Hypertension, CNV and 
Optic Nerve Swelling 
Participants are assessed for CNV at all visits and for intracranial hypertension and optic nerve 
swelling at all visits starting at Month 9. Physical examination is performed at baseline and thyroid 
palpation at all visits except Months 3, 6 and 12. 
The number and percentage of participants with clinically significant physical examination and 
thyroid palpation findings, intracranial hypertension, CNV and optic nerve swelling will be 
summarized as outlined in Table 26. 
13.9 
Laboratory Assessments 
Acute care panel, hepatic panel, complete blood count and thyroid function tests will be performed 
at baseline, Month 9, Month 15 and all visits thereafter. 
Frequency and percentage of participants reporting laboratory abnormalities at baseline will be 
summarized with shift from baseline to each follow-up visit (Table 27). 
13.10 Other Safety Outcomes 
Exploratory analyses and/or descriptive summary statistics of other OCT parameters, 
microperimetry (including macular sensitivity measured using microperimetry) and other 
assessments will be presented as appropriate. 
14.0 
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 plan. Tables and figures will be presented only when adequate amount of data are 
available. Data for some outcomes may not be available to the Coordinating Center at every visit. 
Because of this, these outcomes may not be presented until after study closure. 


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15.0 
QUALITY ASSURANCE PLANS 
To ensure accurate, reliable study results, two statisicians will seperately analyze and compare the 
primary study outcome. All SAS code used to generate primary and secondary outcomes will 
undergo a code audit by an independent project statistician. All protocol tables, figures, listings, 
and reports will also undergo review by a secondary statistician. Documentation of these audits 
will be kept on file at the Coordinating Center. 


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16.0 
REFERENCES 
1. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-
related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;104(1):7-21. 
2. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye 
Study. Ophthalmology. 1992;99(6):933-43. 
3. Edwards AO, Ritter R, 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor 
H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421-4. 
4. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A 
common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes 
individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 
2005;102(20):7227-32. 
5. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor 
H 
variant 
increases 
the 
risk 
of 
age-related 
macular 
degeneration. 
Science. 
2005;308(5720):419-21. 
6. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H 
polymorphism in age-related macular degeneration. Science. 2005;308(5720):385-9. 
7. Tuo J, Ning B, Bojanowski CM, Lin ZN, Ross RJ, Reed GF, et al. Synergic effect of 
polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular 
degeneration predisposition. Proc Natl Acad Sci U S A. 2006;103(24):9256-61. 
8. Cousins SW, Espinosa-Heidmann DG, Csaky KG. Monocyte activation in patients with age-
related macular degeneration: a biomarker of risk for choroidal neovascularization? Arch 
Ophthalmol. 2004;122(7):1013-8. 
9. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C 
and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS 
report no. 8. Arch Ophthalmol. 2001;119(10):1417-36. 


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10. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the 
formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411-31. 
11. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and 
inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye 
Res. 2001;73(6):887-96. 
12. Rodrigues EB. Inflammation in dry age-related macular degeneration. Ophthalmologica. 
2007;221(3):143-52. 
13. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-
Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence 
patterns in age-related macular degeneration. Am J Ophthalmol. 2007;143(3):463-72. 
14. Sunness JS, Margalit E, Srikumaran D, Applegate CA, Tian Y, Perry D, et al. The long-term 
natural history of geographic atrophy from age-related macular degeneration: enlargement of 
atrophy and implications for interventional clinical trials. Ophthalmology. 2007;114(2):271-7. 


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17.0 
MOCK SHELLS 
TABLES 
Table 1. Participant Disposition
Disposition 
BEH 
(N=X) 
N (%)a 
NEI 
(N=X) 
N (%)a 
Total 
(N=X) 
N (%)a 
Enrolled 
x (x) 
x (x) 
x (x) 
 
 
 
 
Run-in Phase (Baseline - Month 9) 
 
 
 
   Discontinued study during run-in phase 
x (x) 
x (x) 
x (x) 
 
AE/intercurrent illness 
x (x) 
x (x) 
x (x) 
 
Death 
x (x) 
x (x) 
x (x) 
 
Insufficient therapeutic response 
x (x) 
x (x) 
x (x) 
 
Lost to follow-up 
x (x) 
x (x) 
x (x) 
 
Participant request/refusal 
x (x) 
x (x) 
x (x) 
 
Early study closure 
x (x) 
x (x) 
x (x) 
 
Protocol deviation 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
   Completed run-in phase 
x (x) 
x (x) 
x (x) 
 
 
 
 
Treatment Phase 
 
 
 
Month 9 – Month 33b 
 
 
 
Initiated treatment at Month 9 
x (x) 
x (x) 
x (x) 
Discontinued study prior to Month 33 
x (x) 
x (x) 
x (x) 
 
AE/intercurrent illness 
x (x) 
x (x) 
x (x) 
 
Death 
x (x) 
x (x) 
x (x) 
 
Insufficient therapeutic response 
x (x) 
x (x) 
x (x) 
 
Lost to follow-up 
x (x) 
x (x) 
x (x) 
 
Participant request/refusal 
x (x) 
x (x) 
x (x) 
 
Early study closure 
x (x) 
x (x) 
x (x) 
 
Protocol deviation 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
Completed Month 33 visit 
x (x) 
x (x) 
x (x) 
Month 33-Month 45c 
 
 
 
Discontinued study after Month 33 and 
prior to Month 45 
x (x) 
x (x) 
x (x) 
 
AE/intercurrent illness 
x (x) 
x (x) 
x (x) 
Death 
x (x) 
x (x) 
x (x) 
Insufficient therapeutic response 
x (x) 
x (x) 
x (x) 
Lost to follow-up 
x (x) 
x (x) 
x (x) 


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Disposition 
BEH 
(N=X) 
N (%)a 
NEI 
(N=X) 
N (%)a 
Total 
(N=X) 
N (%)a 
Participant request/refusal 
x (x) 
x (x) 
x (x) 
Early study closure 
x (x) 
x (x) 
x (x) 
Protocol deviation 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
Completed Month 45 visit 
x (x) 
x (x) 
x (x) 
 
 
 
 
Month 45-Month 57c 
 
 
 
Discontinued study after Month 45 and 
prior to Month 57 
x (x) 
x (x) 
x (x) 
 
AE/intercurrent illness 
x (x) 
x (x) 
x (x) 
 
Death 
x (x) 
x (x) 
x (x) 
 
Insufficient therapeutic response 
x (x) 
x (x) 
x (x) 
 
Lost to follow-up 
x (x) 
x (x) 
x (x) 
 
Participant request/refusal 
x (x) 
x (x) 
x (x) 
 
Early study closure 
x (x) 
x (x) 
x (x) 
 
Protocol deviation 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
Completed Month 57 visit 
x (x) 
x (x) 
x (x) 
Completed study at or after Month 57 
per-protocol 
x (x) 
x (x) 
x (x) 
Discontinued study at or after Month 
57 
x (x) 
x (x) 
x (x) 
AE/intercurrent illness 
x (x) 
x (x) 
x (x) 
Death 
x (x) 
x (x) 
x (x) 
Insufficient therapeutic response 
x (x) 
x (x) 
x (x) 
Lost to follow-up 
x (x) 
x (x) 
x (x) 
Participant request/refusal 
x (x) 
x (x) 
x (x) 
Early study closure 
x (x) 
x (x) 
x (x) 
Protocol deviation 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
a Column header count and denominators are the number of participants in the enrolled population. Percentages are 
rounded to the nearest whole number. 
b Primary outcome is assessed at Month 33. 
c Minimum required follow-up is through Month 45. Common termination date is reached when the last recruited 
participant completes the study through Month 45. Prior to protocol Amendment L (Institutional Review Board 
approved on March 17, 2022), additional follow-up beyond Month 45 may be completed for those participants enrolled 
at the beginning of the study and continue on study until the common termination date. As of protocol Amendment L, 
participants could complete the study per-protocol prior to the common termination date and as early as Month 45 at 
the discretion of the Principal Investigator. 
 


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Table 2. Summary of Demographic Characteristics 
Demographic Characteristics 
BEH 
(N=X)a 
NEI 
(N=X)a 
Total 
(N=X)a 
Gender, N (%) 
 
 
 
      Male 
x (x) 
x (x) 
x (x) 
      Female 
x (x) 
x (x) 
x (x) 
Age Category (years) at Baseline, N (%) 
 
 
 
55-60 
x (x) 
x (x) 
x (x) 
 
61-65 
x (x) 
x (x) 
x (x) 
 
66-70 
x (x) 
x (x) 
x (x) 
 
71-75 
x (x) 
x (x) 
x (x) 
 
76-80 
x (x) 
x (x) 
x (x) 
 
>80 
x (x) 
x (x) 
x (x) 
Age (years) at Baselineb 
 
 
 
      N 
x 
x 
x 
      Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
      Median 
x 
x 
x 
      Range (Min, Max) 
x, x 
x, x 
x, x 
Ethnicity, N (%) 
 
 
 
      Hispanic or Latino 
x (x) 
x (x) 
x (x) 
      Not Hispanic or Latino 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
Race, N (%) 
 
 
 
 
American Indian or Alaskan Native 
x (x) 
x (x) 
x (x) 
 
Asian 
x (x) 
x (x) 
x (x) 
 
Black 
x (x) 
x (x) 
x (x) 
 
Hawaiian or Pacific Islander 
x (x) 
x (x) 
x (x) 
 
White 
x (x) 
x (x) 
x (x) 
      Multiple Race 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
aColumn header count and denominators are the number of participants in the enrolled population at the respective 
sites and overall. Percentages are rounded to the nearest whole number. 
bParticipants over the age of 89 (N=X at BEH, N=X at NEI, and N=X total) are excluded as ages over 89 are 
Protected Health Information (PHI). 


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Table 3. Medical and Ocular History 
Conditions/Procedures 
Study Eye 
(N=X) 
N (%)a 
Fellow Eye 
Total 
Participants 
(N=X) 
N (%)a,d 
Qualifying 
(N=X) 
N (%)b 
Non-Qualifying 
(N=X) 
N (%)c 
Any Medical Condition 
 
 
 
x (x) 
 
Dizzy spells 
 
 
 
x (x) 
      Hypertension 
 
 
 
x (x) 
 
Controlled 
 
 
 
x (x) 
 
Uncontrolled 
 
 
 
x (x) 
 
… 
 
 
 
x (x) 
 
 
 
 
 
Any Ocular Condition 
x (x) 
x (x) 
x (x) 
x (x) 
 
Diabetic retinopathy 
x (x) 
x (x) 
x (x) 
x (x) 
 
Uveitis 
x (x) 
x (x) 
x (x) 
x (x) 
 
… 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
 
 
Any Ocular Procedure 
x (x) 
x (x) 
x (x) 
x (x) 
      Cataract surgery 
x (x) 
x (x) 
x (x) 
x (x) 
      YAG 
x (x) 
x (x) 
x (x) 
x (x) 
 
… 
x (x) 
x (x) 
x (x) 
x (x) 
Percentages are rounded to the nearest whole number. 
aColumn header count and denominators are the number of participants in the enrolled population at all sites. 
bColumn header count and denominators are number of participants in the enrolled population at all sites with qualifying 
fellow eye. 
cColumn header count and denominators are number of participants in the enrolled population at all sites with non-qualifying 
fellow eye. 
dIf a participant reported an ocular condition or procedure in both eyes, the participant will be counted only once in this 
column. 
 


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Table 4. Summary of Participant-Specific Protocol Deviations and Unanticipated Problems 
 
 Number of Participants 
with Events 
 Number of 
Events 
 
BEH 
(N=X) 
N (%)a 
NEI 
(N=X) 
N (%)a 
Total 
(N=X) 
N (%)a 
BEH 
NEI 
Total 
All events 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Protocol deviations 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Unanticipated problems 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
 
 
 
 
 
 
 
Type 
 
 
 
 
 
 
   Minor 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Not Serious 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Serious 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Pending Determination 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
 
 
 
 
 
 
 
Outcome 
 
 
 
 
 
 
   Participant follow-up continues 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Participant follow-up terminated 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Investigational product remains stable 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Investigational product returned or discarded 
x (x) 
x (x) 
x (x) 
xx 
xx 
xx 
   Other 
x (x%) 
x (x%) 
x (x%) 
xx 
xx 
xx 
Prior to July 1, 2019, Investigators classified deviations and unanticipated problems as serious or not serious. Effective July 1 2019, Investigators classify 
deviations and unanticipated problems as minor or major and IRB classifies the major deviations and unanticipated problems as serious or not serious. Pending 
determination category corresponds to those major deviations or unanticipated problems that the IRB is yet to classify as serious or not serious. 
aColumn header count and denominators are the total number of participants enrolled at each site and overall. Percentages are rounded to the nearest whole 
number.  


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Table 5. Summary of Non-Participant Specific Protocol Deviations and Unanticipated 
Problems 
 
 Number of 
Events 
 
BEH 
NEI 
Total 
All events 
xx 
xx 
xx 
   Protocol deviations 
xx 
xx 
xx 
   Unanticipated problems 
xx 
xx 
xx 
 
 
 
 
Type 
 
 
 
   Minor 
xx 
xx 
xx 
   Not Serious 
xx 
xx 
xx 
   Serious 
xx 
xx 
xx 
   Determination Pending 
xx 
xx 
xx 
 
 
 
 
Outcome 
 
 
 
   Participant follow-up continues 
xx 
xx 
xx 
   Participant follow-up terminated 
xx 
xx 
xx 
   Investigational product remains stable 
xx 
xx 
xx 
   Investigational product returned or discarded 
xx 
xx 
xx 
   Other 
xx 
xx 
xx 
Prior to July 1, 2019, Investigators classified deviations and unanticipated problems as serious or not serious. Effective July 1 
2019, Investigators classify deviations and unanticipated problems as minor or major and IRB classifies the major deviations and 
unanticipated problems as serious or not serious. Pending determination category corresponds to those major deviations or 
unanticipated problems that the IRB is yet to classify as serious or not serious. 
 
 
 


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Table 6. IP Compliance 
Site 
Participant ID 
Visit 
Number of 
Days on IP 
 
Expected Number 
of Doses Taken 
Number of Doses 
Taken 
Number of 
Doses Missed 
Compliance 
Ratea 
BEH 
BEH001 
Month 9 to Month 12 
xx 
xx 
xx 
Xx 
x.x 
 
 
Month 12 to Month 15 
xx 
xx 
xx 
xx 
x.x 
 
 
Month 15 to Month 21 
xx 
xx 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
xx 
xx 
x.x 
 
 
Total 
xx 
xx 
xx 
xx 
x.x 
 
 
 
 
 
 
 
 
 
BEH002 
Month 9 to Month 12 
xx 
xx 
xx 
xx 
x.x 
 
 
Month 12 to Month 15 
xx 
xx 
xx 
xx 
x.x 
 
 
Month 15 to Month 21 
xx 
xx 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
xx 
xx 
x.x 
 
… 
… 
… 
… 
… 
… 
… 
NEI 
NEI001 
… 
… 
… 
… 
… 
… 
 
 
… 
… 
… 
… 
… 
… 
 
 
Total 
xx 
xx 
xx 
xx 
x.x 
a Green highlighted cells indicate that the IP compliance rate is <50% between visits for a participant. Yellow highlighted cells (i.e., in “Total” rows) correspond to overall compliance 
rate <50%. Percentages are rounded to the nearest tenth. 
 


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Table 7. Missed Study Procedures 
 
 
 BEH 
 NEI 
 Total 
 
Expecteda 
Missedb 
Percentage 
Missedc 
Expecteda 
Missedb 
Percentage 
Missedc 
Expecteda 
Missedb 
Percentage 
Missedc 
By Participant 
 
 
 
 
 
 
 
 
 
BEH 
 
 
 
 
 
 
 
 
 
BEH001 
xxx 
xxx 
xx.x 
 
 
 
 
 
 
BEH002 
xxx 
xxx 
xx.x 
 
 
 
 
 
 
… 
… 
… 
… 
 
 
 
 
 
 
NEI 
 
 
 
 
 
 
 
 
 
NEI001 
 
 
 
xxx 
xxx 
xx.x 
 
 
 
NEI002 
 
 
 
xxx 
xxx 
xx.x 
 
 
 
… 
 
 
 
… 
… 
… 
 
 
 
By Procedure 
 
 
 
 
 
 
 
 
 
Acute Care Panel 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
Adverse Event Assessment 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
Total 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
a The expected number of procedures is defined based on the study flowsheet included in the protocol. 
b Procedures not completed are defined when the site reports a missed procedure or when the protocol monitors note missed procedures at a site visit. 
c Percentages are rounded to the nearest tenth. 
 
 
 


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Table 8. Missed and Out of Window Study Visits 
Site 
Participant 
ID 
Number of 
Expected 
Study Visits 
Missed Study Visits 
Out of Window Study Visits 
 
Number 
Percentage 
Visits 
Number 
Percentage 
Visits 
BEH 
BEH001 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
BEH002 
xx 
xx 
xx 
xxx 
xx 
x.x 
xx 
 
… 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
Total 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
 
 
 
 
 
 
 
 
NEI 
NEI001 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
NEI002 
xx 
xx 
xx 
xxx 
xx 
x.x 
xx 
 
… 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
Total 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 
 
 
 
 
 
 
 
 
All 
Total 
xx 
xx 
xx 
 
xx 
x.x 
xx 
 


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Table 9. Analysis of Primary Outcome of Difference in Rates of Change in Appropriately Transformed GA Area During Run-in and 
Treatment Phases as Determined Using FAF Images and Corresponding Sensitivity and Exploratory Analyses 
Population Used, Assumption 
Study Eye 
Qualifying Fellow Eye 
Study Eye +  
Qualifying Fellow Eye 
Coefficient 
SE 
p-value Coefficient 
SE 
p-value Coefficient 
SE 
p-value 
Enrolled population, MCAR 
 
 
 
 
 
 
 
 
 
 
GA progression rate during run-in phase 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
Enrolled population, MI 
 
 
 
 
 
 
 
 
 
 
GA progression rate during run-in phase 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
Per-protocol population 1 
 
 
 
 
 
 
 
 
 
 
GA progression rate during run-in phase 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
Per-protocol population 2, MCAR 
 
 
 
 
 
 
 
 
 
 
GA progression rate during run-in phase 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Per-protocol population 3, MCAR 
 
 
 
 
 
 
 
 
 
 
GA progression rate during run-in phase 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Abbreviations: SE - standard error, MCAR - missing completely at random, MI - multiple imputation 
All analyses are based on appropriately transformed GA area. 
Change in appropriately transformed GA area during run-in phase is assessed from Baseline to Month 9 and during treatment phase is assessed from Month 9 to Month 
33. 
Cells highlighted in green correspond to the primary outcome analysis; cells highlighted in yellow correspond to sensitivity analyses and the remaining correspond to 
exploratory analyses. 
 


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Table 10. Analysis of Secondary Outcome of Difference in Rates of Change in Appropriately Transformed GA Area During Run-in and 
Treatment Phases as Determined Using FAF Images and Corresponding Exploratory Analyses 
Population Used, Assumption 
Study Eye 
Qualifying Fellow Eye 
Study Eye +  
Qualifying Fellow Eye 
Mean (95% CI) 
p-value 
Mean (95% CI) 
p-value 
Mean (95% CI) 
p-value 
Enrolled population, MCAR 
 
 
 
 
 
 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
 
 
 
 
 
 
 
Enrolled population, MI 
 
 
 
 
 
 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
 
 
 
 
 
 
 
Per-protocol population 1 
 
 
 
 
 
 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
 
 
 
 
 
 
 
Per-protocol population 2, MCAR 
 
 
 
 
 
 
 
Difference in GA progression rate 
 
between run-in and treatment phases 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
x.xx (x.xx, x.xx) 
x.xx 
Abbreviations: MCAR - missing completely at random, MI - multiple imputation 
All analyses are based on appropriately transformed GA area. 
Mean (95% CI) and two-sided p-value from Student’s paired t-test conducted at type I error rate of 5%. 
Cells highlighted in yellow correspond to secondary analyses and the remaining correspond to exploratory analyses. 
 


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Table 11. Analysis of Secondary Outcome of Difference in Rates of Change in Appropriately Transformed GA Area During 
Run-in and Treatment Phases as Determined Using CFP and Corresponding Exploratory Analyses  
This table will be similar to Table 9 and may not include all analyses outlined in Table 9. 
Table 12. Analysis of Secondary Outcome of Change in BCVA 
 
Eye 
Statistic 
Rate of Change during Run-in Phase 
Rate of Change during 
Treatment Phase 
 Month 9 – Baseline 
Month 33 – Month 9 
Study Eye 
N 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
 
Difference (95% CI)a 
 
x.x (x.x, x.x) 
 
p-valueb 
 
x.xx 
 
Participants with 3-line 
worsening, N (%) 
x (x) 
x (x) 
 
p-value3 
 
x.xx 
Qualifying Fellow Eye 
N 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
 
Difference (95% CI)a 
 
x.x (x.x, x.x) 
 
p-valueb 
… 
x.xx 
 
Participants with 3-line 
worsening, N(%) 
x (x%) 
x (x) 
 
p-valuec 
 
x.xx 
Study Eye and Qualifying Fellow Eye … 
… 
… 
 
… 
… 
… 
Non-Qualifying Fellow Eye 
… 
… 
… 
 
… 
… 
… 
aDifference between mean rate of change during treatment phase vs. mean rate of change during run-in phase. 
ap-value from Student’s paired t-test corresponding to the difference in mean rate of change during the treatment phase vs. run-in phase. 
bp-value from Chi-squared test or Fisher’s exact test corresponding to the difference in proportions of participants with 3-line worsening between the treatment phase and run-in 
phase. 


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Table 13. Analysis of Secondary Outcome of Change in LLVA 
This table will be similar to Table 12. This table will not include statistics for non-qualifying fellow 
eye and proportions of participants. 
Table 14. Analysis of Secondary Outcome of Change in Central Retinal Thickness on OCT 
This table will be similar to Table 12. This table will not include statistics for non-qualifying fellow 
eye and proportions of participants. 
 


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Table 15. Summary of BCVA Total Letters Read Over Time 
Visit 
BCVA Total Letters Read 
Change from Baseline 
Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Non-
Qualifying 
Fellow Eye 
Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Non-
Qualifying 
Fellow Eye 
Baseline 
 
 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
 
Median 
x 
x 
x 
x 
 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
Month 3 
 
 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
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.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
Gain of >=15 letters, N (%)a 
 
 
 
 
x (x) 
x (x) 
x (x) 
x (x) 
 
Loss of 15 to 30 letters, N (%)a 
 
 
 
 
x (x) 
x (x) 
x (x) 
x (x) 
 
Loss of >30 letters, N (%)a 
 
 
 
 
x (x) 
x (x) 
x (x) 
x (x) 
Month X 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Month 57 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
aDenominators are the number of applicable eyes in the safety population with data at the given visit for the given eye(s). 


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Table 16. Summary of Ocular Surface Changes and Inflammation Over Time 
Visit 
Ocular Surface Changes 
Inflammation 
Study 
Eye 
n/N 
(%) 
Qualifying 
Fellow Eye 
n/N (%) 
Study Eye + 
Qualifying 
Fellow Eye 
n/N (%) 
Non-
Qualifying 
Fellow Eye 
n/N (%) 
Study Eye 
n/N (%) 
Qualifying 
Fellow Eye 
n/N (%) 
Study Eye + 
Qualifying 
Fellow Eye 
n/N (%) 
Non-
Qualifying 
Fellow Eye 
n/N (%) 
At least once 
during the study x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
Month 9 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
Month 12 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
Month 15 
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) 
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) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
Month 57 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
x/X (x) 
Denominators are the number of applicable eyes for participants in the safety population with data at the given visit for the given eye(s). 
Table 17. Summary of Treatment-Emergent Adverse Events 
 
Participants with 
Events 
N (%)a 
Number of 
Events 
N 
All AEs 
x (x) 
x 
Serious Adverse Events 
x (x) 
x 
 
 
 
Severity 
 
 
 Mild 
x (x) 
x 
 Moderate 
x (x) 
x 
 Severe 
x (x) 
x 
 Life-threatening 
x (x) 
x 
 Death 
x (x) 
x 
 
 
 
Ocular Specification 
 
 
 Non-ocular 
x (x) 
x 
 Study Eye 
x (x) 
x 
 Qualifying Fellow Eye 
x (x) 
x 
 Fellow Eye 
x (x) 
x 
 
 
 
Relation to IP 
 
 
 Related 
x (x) 
x 
 Not Related 
x (x) 
x 
aDenominators are the number of participants in the safety population. Percentages are rounded 
to the nearest whole number. 
 
 
 


GA MIN SAP 
March 21, 2023 
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Table 18. Summary of Treatment-Emergent Adverse Events 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 
Total 
x (x) 
x 
 
 
 
SOC1 
x (x) 
x 
 
PT1 
x (x) 
x 
 
PT2 
x (x) 
x 
SOC2 
x (x) 
x 
 
PT1 
x (x) 
x 
 
PT2 
x (x) 
x 
… 
x (x) 
x 
… 
x (x) 
x 
a MedDRA version XX.X. 
b SOCs are presented in descending order of number of events reported; PTs within each SOC 
are also presented in descending order of number of events reported. 
c Denominators are the number of participants in the safety population. Percentages are rounded 
to the nearest whole number. 
Table 19. Summary of LLVA Total Letters Read Over Time 
This table will be similar to Table 16. Rows corresponding to number and percentage of 
participants experiencing a change of 15 letters or more or loss of >30 letters from baseline as well 
as statistics for non-qualifying fellow eye will be excluded. 
Table 20. Summary of IOP Over Time 
This table will be similar to Table 16. Rows corresponding to number and percentage of 
participants experiencing change from baseline in letters read will be excluded. A row 
summarizing number and percentage of participants with IOP > 30 mmHg or an increase an 
increase from baseline of > 10mmHg will be added to the table. 


GA MIN SAP 
March 21, 2023 
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Table 21. Summary of FAF Assessments at Baseline and Months 9 and 33
Visit 
Study Eye 
n/N (%) 
Qualifying 
Fellow Eye  
n/N (%) 
Study Eye + 
Qualifying Fellow Eye 
n/N (%) 
Baseline 
 
 
 
Decreased AF present 
 
 
 
 
No 
x/X (x) 
x/X (x) 
x/X (x) 
 
Yes 
x/X (x) 
x/X (x) 
x/X (x) 
 
Questionable 
x/X (x) 
x/X (x) 
x/X (x) 
Location of definite decreased AF 
 
 
 
 
Not subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Increased AF present 
 
 
 
 
No 
x/X (x) 
x/X (x) 
x/X (x) 
 
Yes 
x /X (x) 
x/X (x) 
x/X (x) 
 
Questionable 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Junctional AF pattern 
 
 
 
 
None 
x/X (x) 
x/X (x) 
x/X (x) 
 
Focal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Banded 
x/X (x) 
x/X (x) 
x/X (x) 
 
Patchy 
x/X (x) 
x/X (x) 
x/X (x) 
 
Diffuse 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Fine granular 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Branching 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Trickling 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Reticular 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Fine granular with punctuated spots 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Significant medical findings 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Month 9 
 
 
 
Decreased AF present 
 
 
 
 
No 
x/X (x) 
x/X (x) 
x/X (x) 
 
Yes 
x/X (x) 
x/X (x) 
x/X (x) 
 
Questionable 
x/X (x) 
x/X (x) 
x/X (x) 
Location of definite decreased AF 
 
 
 
 
Not subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Increased AF present 
 
 
 
 
No 
x/X (x) 
x/X (x) 
x/X (x) 
 
Yes 
x/X (x) 
x/X (x) 
x/X (x) 
 
Questionable 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
 
 


GA MIN SAP 
March 21, 2023 
Table 21. Summary of FAF Assessments at Baseline and Months 9 and 33 (continued) 
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Visit 
Study Eye  
n/N (%) 
Qualifying 
Fellow Eye  
n/N (%) 
Study Eye + 
Qualifying Fellow Eye 
n/N (%) 
Junctional AF pattern 
 
 
 
 
None 
x/X (x) 
x/X (x) 
x/X (x) 
 
Focal 
x/X (x) 
x/X (x) 
x/X (x) 
 
Banded 
x/X (x) 
x/X (x) 
x/X (x) 
 
Patchy 
x/X (x) 
x/X (x) 
x/X (x) 
 
Diffuse 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Fine granular 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Branching 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Trickling 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Reticular 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
Fine granular with punctuated spots 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Significant medical findings 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Month 33 
 
 
 
… 
 
 
 
… 
 
 
 
… 
 
 
 
Denominators are the number of applicable eyes for participants in the safety population with data at the given visit for the 
given eye(s). Participant eyes for which the FAF images could not be graded are included in the denominators. Participant 
eyes for which the assessment was not applicable or were not evaluated are excluded from this table.  
 


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March 21, 2023 
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Table 22. Summary of Total Areas of Decreased and Increased AF and Scaled Distance from Foveal Center as Assessed by FAF at Baseline 
and Months 9 and 33
Visit 
FAF Assessments 
Changea 
Study 
Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Baseline 
 
 
 
 
 
 
Total area of decreased AF (definite + 
questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
Total area of decreased AF (definite) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
Total area of decreased AF (questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
Total area of increased AF (definite + 
questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
Total area of increased AF (definite) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
 


GA MIN SAP 
March 21, 2023 
Table 22. Summary of Total Areas of Decreased and Increased AF and Scaled Distance from Foveal Center as Assessed by FAF at Baseline 
and Months 9 and 33 (continued) 
Version 4.0 
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Visit 
FAF Assessments 
Changea 
Study 
Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Total area of increased AF (questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
Distance from foveal center to nearest point on 
retina not showing DDAFb, QDAFc or IAFd 
(mm)b 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
Month 9 
 
 
 
 
 
 
Total area of decreased AF (definite + 
questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Total area of decreased AF (definite) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Total area of decreased AF (questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 


GA MIN SAP 
March 21, 2023 
Table 22. Summary of Total Areas of Decreased and Increased AF and Scaled Distance from Foveal Center as Assessed by FAF at Baseline 
and Months 9 and 33 (continued) 
Version 4.0 
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Page 51 
Visit 
FAF Assessments 
Changea 
Study 
Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Total area of increased AF (definite + 
questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Total area of increased AF (definite) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Total area of increased AF (questionable) (mm2) 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
Distance from foveal center to nearest point on 
retina not showing DDAFb, QDAFc or IAFd 
(mm)e 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
Month 33 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
aChange is calculated from baseline at Month 9 and from Month 9 at Month 33. 
b DDAF – definite decreased autofluorescence 
c QDAF – questionable decreased autofluorescence 
d IAF – increased autofluorescence 
eIf linear measurement correction factor was used, then scaled values are used in the analysis. 


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Table 23. Summary of CFP Assessments at Baseline and Months 9 and 33
Visit/Parameter 
Study Eye 
Qualifying Fellow Eye 
Study Eye +  
Qualifying Fellow Eye 
No 
N (%) 
Yes  
N (%) 
Questionable  
N (%) 
No  
N (%) 
Yes  
N (%) 
Questionable  
N (%) 
No  
N (%) 
Yes  
N (%) 
Questionable 
N (%) 
Baseline 
 
 
 
 
 
 
 
 
 
Geographic Atrophy 
 
 
 
 
 
 
 
 
 
 
Macular GA present 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
All sites of macular GA 
 
visible within the field of 
 
view of Field 2 fundus 
 
photos  
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
 
 
 
 
 
 
 
CNV 
 
 
 
 
 
 
 
 
 
Evidence of CNV 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Hemorrhage 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Lipid 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Fluid 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Subretinal fibrosis 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Fibrosis subfoveal 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other CNV evidence 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
 
 
 
 
 
 
 
Other Features 
 
 
 
 
 
 
 
 
 
 
RPE hyperplasia/ 
 
pigment 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
RPE depigmentation 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Pattern dystrophy 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Pseudovitelliform lesion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Vitreomacular traction 
 
(ERM, MH, other) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Evidence of laser or 
 
photodynamic therapy to 
 
the macula 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other disease likely to 
 
confound study outcome 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 


GA MIN SAP 
March 21, 2023 
Table 23. Summary of CFP Assessments at Baseline and Months 9 and 33 (continued) 
 
Version 4.0 
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Page 53 
Visit/Parameter 
Study Eye 
Qualifying Fellow Eye 
Study Eye +  
Qualifying Fellow Eye 
No  
N (%) 
Yes  
N (%) 
Questionable  
N (%) 
No  
N (%) 
Yes  
N (%) 
Questionable  
N (%) 
No  
N (%) 
Yes  
N (%) 
Questionable 
N (%) 
 
Other disease or finding 
 
unlikely to confound 
 
study outcome 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Significant medical 
 
finding 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
 
 
 
 
 
 
 
 
 
Month 9 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 33 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Denominators are the number of applicable eyes for participants in the safety population with data at the given visit for the given eye(s). Participant eyes for 
which the CFP images could not be graded are included in the denominators. Participant eyes for which the assessment was not applicable or were not evaluated 
are excluded from this table. 
 


GA MIN SAP 
March 21, 2023 
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Table 24. Summary of Macular GA and CNV as Assessed by CFP at Baseline and Months 9 and 33
Visit 
CFP Assessments 
Changea 
Study 
Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
Baseline 
 
 
 
 
 
 
Macular GA location, n/N (%)b 
 
 
 
 
 
 
 
Not subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
Total area of macular GA (mm2)c 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
Distance from foveal center to nearest 
uninvolved retina (mm)c 
 
 
 
 
 
 
 
N 
x 
x 
x 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
 
 
 
Median 
x 
x 
x 
 
 
 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
CNV location in relation to fovea, n/N (%)b 
 
 
 
 
 
 
 
Not subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
 
 
 
 
 
 
Month 9 
 
 
 
 
 
 
Macular GA location, n/N (%)b 
 
 
 
 
 
 
 
Not subfoveal 
x/N (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
Total area of macular GA (mm2)c 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Distance from foveal center to nearest 
uninvolved retina (mm)c 
 
 
 
 
 
 


GA MIN SAP 
March 21, 2023 
Table 24. Summary of Macular GA and CNV as Assessed by CFP at Baseline and Months 9 and 33 (continued) 
Version 4.0 
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Page 55 
Visit 
CFP Assessments 
Changea 
Study 
Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye Study Eye 
Qualifying 
Fellow Eye 
Study Eye + 
Qualifying 
Fellow Eye 
 
N 
x 
x 
x 
x 
x 
x 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
 
Median 
x 
x 
x 
x 
x 
x 
 
Range (Min, Max) 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
CNV location in relation to fovea, n/N (%)b 
 
 
 
 
 
 
 
Not subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Probably subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
Subfoveal 
x/X (x) 
x/X (x) 
x/X (x) 
 
 
 
 
 
 
 
 
 
 
Month 33 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
aChange is calculated from Baseline at Month 9 and from Month 9 at Month 33. 
bDenominators are the number of applicable eyes for participants in the safety population with data at the given visit for the given eye(s). 
Percentages are rounded to the nearest whole number. Participant eyes for which the CFP images could not be graded are included in the 
denominators. Participant eyes for which the assessment was not applicable or were not evaluated are excluded from this table. 
cIf correction factor was used, then scaled values are used in the analysis. 
 
 


GA MIN SAP 
March 21, 2023 
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Table 25. Summary of OCT Parameters Over Time 
This table will be similar to Table 16. Rows corresponding to number and percentage of participants experiencing a change of 15 letters or more or 
loss of >30 letters from baseline as well as statistics for non-qualifying fellow eye will be excluded. 


GA MIN SAP 
March 21, 2023 
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Table 26. Results of Physical Examination, Thyroid Palpation, Intracranial Hypertension, CNV and Optic Nerve Swelling Assessments Over 
Time 
Visit 
Significant Findings 
Signs of 
Intracranial 
Hypertension 
n/N (%)a 
CNV 
Optic Nerve Swelling 
Physical 
Examination 
n/N (%)a 
Thyroid 
Palpation 
n/N (%)a 
Study 
Eye 
n/N 
(%)b 
Qualifying 
Fellow Eye 
n/N (%)b 
Study Eye + 
Qualifying 
Fellow Eye 
n/N (%)b 
Non-
Qualifying 
Fellow Eye 
n/N (%)b 
Study 
Eye n/N 
(%)b 
Qualifying 
Fellow Eye 
n/N (%)b 
Study Eye + 
Qualifying 
Fellow Eye 
n/N (%)b 
Non-
Qualifying 
Fellow Eye 
n/N (%)b 
Baseline 
x/X (x) 
x/X (x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least once during 
a follow-up visit 
 
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) 
x/X (x) 
Month 9 
 
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) 
x/X (x) 
Month 12 
 
 
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) 
… 
 
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) 
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) 
x/X (x) 
x/X (x) 
Month 57 
 
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) 
x/X (x) 
aDenominators are the number of participants in the safety population with data at the given visit. 
bDenominators are the number of applicable eyes for participants in the safety population with data at the given visit for the given eye(s) 
 
 


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Table 27. Summary of Laboratory Assessments Over Time 
Visit 
Participants with 
Laboratory 
Assessments Done 
Na 
Abnormal 
Laboratory 
Assessments 
N (%)b 
Any Change 
from Baseline 
N (%)b 
Clinically Significant 
Change from Baseline 
N (%)b 
Baseline 
x 
x (x) 
 
 
Month 9 
x 
 
x (x) 
x (x) 
Month 15 
x 
 
x (x) 
x (x) 
Month 21 
x 
 
x (x) 
x (x) 
... 
x 
 
x (x) 
x (x) 
… 
x 
 
x (x) 
x (x) 
 
x 
 
x (x) 
x (x) 
Month 57 
x 
 
x (x) 
x (x) 
aParticipants in the safety population with laboratory assessment data at the given visit. 
bDenominators are the number of participants in the safety population with laboratory assessment data at the given 
visit. Percentages are rounded to the nearest whole number. 
Listings 
Listing 1. Demographic Information by Participant 
Site 
Participant 
ID 
Registration 
Date 
Study 
Eye* 
Age 
Gender 
Race 
Ethnicity 
BEH 
BEH001 
mm/dd/yy 
xx* 
xx 
xxx 
xxx 
xxx 
 
BEH002 
mm/dd/yy 
xx 
xx 
xxx 
xxx 
xxx 
 
… 
mm/dd/yy 
xx* 
xx 
xxx 
xxx 
xxx 
NEI 
NEI001 
mm/dd/yy 
xx* 
xx 
xxx 
xxx 
xxx 
 
… 
mm/dd/yy 
xx 
xx 
xxx 
xxx 
xxx 
*Participant with qualifying fellow eye are indicated by an asterisk (*) 
 
 


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Listing 2. Rate of Change in Appropriately Transformed GA Area During Run-in and Treatment Phases as Determined Using FAF Images 
(Study Eye) 
Site 
Participant 
ID 
Appropriately Transformed GA 
Area 
Rate of Change in Appropriately Transformed GA Area 
Baseline 
Month 9 
Month 33 
During Run-in Phase: 
Month 9-Baseline 
During Treatment Phase: 
Month 33-Month 9 
Between Treatment and 
Run-in Phases 
BEH 
BEH001 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
BEH002 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
NEI 
NEI001 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Listing 3. Rate of Change in Appropriately Transformed GA Area During Run-in and Treatment Phases as Determined Using CFP 
Site 
Participant 
ID 
Eye 
Appropriately Transformed GA 
Area 
Rate of Change in Appropriately Transformed GA Area 
Baseline 
Month 9 
Month 33 
During Run-in Phase: 
Month 9-Baseline 
During Treatment Phase: 
Month 33-Month 9 
Between Treatment and 
Run-in Phases 
BEH 
BEH001 
Study eye 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Qualifying 
fellow eye 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Both 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
BEH002 
Study eye 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Qualifying 
fellow eye 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Both 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
NEI 
NEI001 
… 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
… 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 


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Listing 4. Rate of Change in BCVA During Run-in and Treatment Phases 
This listing will be similar to Listing 3. Participants with 3-line worsening during either phase will be highlighted. 
Listing 5. Rate of Change in LLVA During Run-in and Treatment Phases 
This listing will be similar to Listing 3. 
Listing 6. Rate of Change in Central Retinal Thickness on OCT During Run-in and Treatment Phases 
This listing will be similar to Listing 3. 


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Figures
Figure 1. Consort Diagram of Participant Disposition
g
g


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18.0 
PRIMARY OUTCOME ANALYSIS PRESENTATIONS 
The primary outcome analysis report, to be completed after the final participant has completed 
their primary outcome visit (Month 33), will include all presentations included in the DSMC 
meeting immediately preceding the primary outcome analysis DSMC meeting as well as the SAP 
TFLs included in Table 28. Modifications to be made to TFLs prior to being included in the 
primary outcome analysis report, where applicable, are also outlined in Table 28. 
  
Table 28. SAP-Specific Tables, Figures, and Listings (TFLs) to be Included in Primary 
Outcome Analysis Report 
SAP TFL 
Number 
SAP TFL Title 
Modifications 
Table 9a 
Analysis of Primary Outcome of Difference 
in Rates of Change in Appropriately 
Transformed GA Area During Run-in and 
Treatment Phases as Determined Using FAF 
Images 
Will include analyses for the study eye 
related to the enrolled population under the 
MCAR assumption.  
Table 10a 
Analysis of Secondary Outcomes of 
Difference in Rates of Change in 
Appropriately Transformed GA Area During 
Run-in and Treatment Phases as Determined 
Using FAF Images 
Will include analyses for the study eye 
related to the enrolled population under the 
MCAR assumption.  
Table 11a 
Analysis of Secondary Outcome of 
Difference in Rates of Change in 
Appropriately Transformed GA Area During 
Run-in and Treatment Phases as Determined 
Using CFP Images 
Will include analyses for the study eye 
related to the enrolled population under the 
MCAR assumption.  
Table 12 
Analysis of Secondary Outcome of Change 
in BCVA 
 
Table 13 
Analysis of Secondary Outcome of Change 
in LLVA 
 
Table 14 
Analysis of Secondary Outcome of Change 
in Central Retinal Thickness on OCT 
 
Listing 2 
Rate of Change in Appropriately 
Transformed GA Area During Run-in and 
Treatment Phases as Determined Using FAF 
Images (Study Eye) 
 
Listing 3 
Rate of Change in Appropriately 
Transformed GA Area During Run-in and 
Treatment Phases as Determined Using CFP 
 
Listing 4 
Rate of Change in BCVA During Run-in and 
Treatment Phases 
 
Listing 5 
Rate of Change in LLVA During Run-in and 
Treatment Phases 
 
Listing 6 
Rate of Change in Central Retinal Thickness 
on OCT During Run-in and Treatment 
Phases 
 
aSAP TFL title modified for accuracy based on content of TFL to be included in primary outcome analysis report