Conditions: Stargardt Disease Macular Atrophy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is a pharmacodynamics study of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease.

Detailed description:
This is a multicenter, randomized, masked study to characterize the pharmacodynamics, safety and tolerability of emixustat in subjects with macular atrophy secondary to Stargardt disease.

Arms:
arm 1: lowest dose of once-daily oral emixustat arm 2: middle dose of once-daily oral emixustat arm 3: highest dose of once-daily oral emixustat

Interventions: intervention 1: Emixustat
Intervention descriptions: intervention 1: Once daily, tablet for oral administration

Protocol document:
Prot_SAP_000.pdf: 
Acucela Inc.
Clinical Study Protocol
Study 4429-204, Amendment 1
13 July 2017
PROTOCOL TITLE:
A Phase 2a Multicenter, Randomized, Masked Study
Evaluating the Pharmacodynamics of Emixustat
Hydrochloride in Subjects with Macular Atrophy
Secondary to Stargardt Disease
PROTOCOL NUMBER:
4429-204
NAME OF TEST ARTICLE:
Emixustat hydrochloride
INDICATION:
Stargardt Disease
DEVELOPMENT PHASE:
Phase 2a
STUDY DESIGN:
Multicenter, randomized, masked, parallel-group
SPONSOR:
Acucela Inc.
818 Stewart St., Suite 1110
Seattle, WA 98101
DATE OF PROTOCOL:
Original: 28 September 2016
Amendment 1: 13 July 2017
The information contained in this document, particularly unpublished data, is the property or under control of
Acucela Inc., and is provided to you in confidence as an Investigator, potential Investigator, or consultant, for
review by you, your staff, and an applicable Institutional Review Board or Independent Ethics Committee.  The
information is only to be used by you in connection with authorized clinical studies of the investigational drug
described in the protocol.  You will not disclose any of the information to others without written authorization
from Acucela Inc., except to the extent necessary to obtain informed consent from those persons to whom the
drug may be administered.
This study will be conducted in accordance with the International Council for Harmonisation guideline E6 (R1):
Good Clinical Practice: Consolidated Guideline and the principles of the World Medical Association
Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects 1964, including
all amendments and Notes of Clarification.
NCT NUMBER: 
        03033108


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1
Sponsor Signature Page
Protocol Number:
4429-204
Protocol Title:
A Phase 2a Multicenter, Randomized, Masked Study
Evaluating the Pharmacodynamics of Emixustat Hydrochloride
in Subjects with Macular Atrophy Secondary to Stargardt
Disease
Approved by:


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2
Key Roles and Contacts
Key roles may be updated by written notification to the clinical sites without a protocol
amendment.
Sponsor:
Acucela Inc.
818 Stewart St., Suite 1110
Seattle, WA 98101
Phone: 206-805-8300


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3
Protocol Summary
Protocol Number:
4429-204
Protocol Title:
A Phase 2a Multicenter, Randomized, Masked Study
Evaluating the Pharmacodynamics of Emixustat
Hydrochloride in Subjects with Macular Atrophy
Secondary to Stargardt Disease
Phase:
Phase 2a
Study Objectives
Primary:
To characterize the pharmacodynamics (PD) of emixustat
hydrochloride (emixustat) in subjects with macular
atrophy (MA) secondary to Stargardt disease (STGD).
Secondary:
To evaluate the safety and tolerability of emixustat when
administered orally for 1 month.
Study Population:
Subjects who have MA secondary to STGD.
Study Design:
This is a multicenter, randomized, masked study to
evaluate the PD and safety and tolerability of emixustat in
subjects with MA secondary to STGD.
Subjects will be randomly assigned to 1 of 3 treatment
arms in a 1:1:1 ratio.  Treatment arms include:

Emixustat 2.5 mg

Emixustat 5 mg

Emixustat 10 mg
Subjects will take study drug once daily (QD) in the
evening for 1 month.
Number of Subjects:
Approximately 30 subjects will be enrolled, with a goal of
having 24 subjects (8 per treatment arm) complete the
masked treatment phase of the study.
Inclusion Criteria:
Subjects who meet all of the following criteria at
Screening and Baseline (unless otherwise indicated) may
be eligible for inclusion in the study:
1. Males or females, age ≥18 years.
2. Clinical diagnosis of MA secondary to STGD in one or
both eyes as determined by the Investigator and
confirmed by the central image reading center.
3. At least 2 pathogenic mutations of the ABCA4 gene.
If only one ABCA4 allele has a pathogenic mutation,


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the subject must have a typical STGD phenotype (ie, at
least one eye has flecks at the level of the retinal
pigment epithelium [RPE] typically seen in STGD)
and be approved for enrollment by the Sponsor.
4. Total area of MA (definitely decreased
autofluorescence plus questionably decreased
autofluorescence) in the study eye equal to 1.25 - 26
mm2 (~0.5 – 10.25 disc areas) in size as determined by
the central image reading center’s assessment of
fundus autofluorescence (FAF) imaging at Screening.
5. The entire lesion must be completely visualized on the
macula-centered image (Field 2 –Macula Image).
6. Early Treatment Diabetic Retinopathy Study (ETDRS)
best-corrected visual acuity (BCVA) of ≥20 letters
(approximately ≥20/400 Snellen) in the study eye.
7. Adequate clarity of ocular media and adequate
pupillary dilation to permit good quality imaging of
MA in the study eye as determined by the Investigator.
8. Able and willing to provide written informed consent
before undergoing any study-related procedures.
9. Able to reliably administer oral medication by self or
with available assistance.
Exclusion Criteria:
Subjects will be excluded from participation in the study if
they meet any of the following criteria at Screening or
Baseline (unless otherwise indicated):
1. Macular atrophy associated with a condition other than
STGD in either eye.
2. Presence in either eye of an active ocular disease that
in the opinion of the Investigator compromises or
confounds visual function, including, but not limited
to, choroidal neovascularization, diabetic retinopathy,
uveitis, other macular diseases, or uncontrolled
glaucoma/ocular hypertension.
3. History of any intraocular or ocular surface surgery in
either eye within 3 months of Screening.
4. Current or previous participation in an interventional
study to treat STGD using gene therapy or stem cell
therapy at any time, or participation in an


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interventional study of a vitamin A derivative ≤3
months prior to screening.
5. Known serious hypersensitivity to emixustat or any of
the excipients in emixustat tablets (ie, silicified
microcrystalline cellulose, pregelatinized starch,
colloidal silicon dioxide, and stearic acid).
6. Prohibited medications:  Systemic use of a strong
inducer of, or a strong or moderate inhibitor of,
cytochrome P450 2D6 (CYP2D6) beginning within
4 weeks prior to Screening or between Screening and
Baseline, or planned use during the study period.
7. Any of the following laboratory abnormalities at
Screening:
a.
Aspartate transaminase (AST)/alanine
transaminase (ALT) > 2.5 × upper limit of normal
(ULN).
b. Total bilirubin > 1.5 × ULN.
c.
Estimated glomerular filtration rate (eGFR)
< 60 mL/min/1.73 m2.
d. Impaired hematologic function:  hemoglobin
< 10 g/dL; neutrophil count < 1.6 × 109/L; or
platelet count < 100 × 109/L.
Any laboratory screening test that meets the
abnormality criteria stated above can be repeated once
within the 30-day period from Screening to Baseline.
8. Participation in any study using an investigational drug
within 5 half-lives (of the investigational drug) of
Screening, or, if the half-life is not known, within
30 days of Screening.
9. Participation in any study of an investigational device
within 60 days of Screening.
10. Anticipated participation during the study period in
any other study using an investigational study drug or
interventional device.
11. Presence of other medical or ophthalmic disease,
physical examination finding, or clinical laboratory
finding that in the opinion of the Investigator
contraindicates the use of an investigational drug;
places the subject at risk by participating in the study;


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might interfere with the evaluation of the PD or safety
of emixustat; negatively impacts subject compliance
with the protocol; confounds the ability to interpret
data from the study; or jeopardizes the subject’s ability
to complete the protocol.
12. Current or history of cancer (except for adequately
treated basal cell or squamous cell carcinoma of the
skin) within 1 year of Screening.
13. History of myocardial infarction, stroke, unstable
ischemic heart disease, uncontrolled cardiac
arrhythmia, or hospitalization for congestive heart
failure within 6 months of Screening.
14. Anticipated hospitalization for a medical/surgical
procedure(s) that could result in interruption/premature
cessation of study treatment or participation.
15. Electrocardiogram with a clinically significant
abnormal finding (eg, acute ischemia, bundle branch
block) or a QT interval, corrected for heart rate by
Bazett’s formula (QTcB) or Fridericia’s formula
(QTcF), of > 460 milliseconds (msec) for men and
> 470 msec for women at Screening.
16. Female subjects who are pregnant or lactating.
17. Female subjects of childbearing potential (ie, not
postmenopausal for at least 2 years and not surgically
sterile) who are not willing to practice a medically
accepted method of birth control with their non-
surgically sterile male sexual partner from Screening
through 30 days after the final dose of study drug.
Medically accepted methods of birth control include
abstinence, hormonal contraceptives, nonhormonal
intrauterine contraceptive device with spermicide,
condom with spermicide, contraceptive sponge with
spermicide, diaphragm with spermicide, or cervical
cap with spermicide.
18. Male subjects who are not surgically sterile and are not
willing to practice a medically accepted method of
birth control with their female partner of childbearing
potential (as listed above) from Screening through
30 days after the final dose of study drug.


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Study Eye Determination:
The study eye will be determined as the eye that meets all
of the inclusion criteria and none of the exclusion criteria.
If both eyes qualify, the eye with the larger MA lesion area
will be selected as the study eye.  If both eyes qualify and
are equal in MA lesion area, the right eye will be selected
as the study eye.  The study eye will be determined by the
Investigator; MA lesion characteristics will be confirmed
by the central image reading center.
Test Product, Dose, and
Mode of Administration:
Emixustat (2.5 mg, 5 mg, and 10 mg) tablets will be
packaged in identical-appearing, tamper proof, blister
packaging to maintain masking.
Study drug will be taken orally QD in the evening for
1 month.
Study Procedures:
The scheduled visits include Screening (within 30 days
prior to Baseline), Baseline (Day 1), and End of Treatment
(Month 1).  A Study Exit visit will be performed 30 days
after the End of Treatment (Month 1) visit (30 days after
the last dose of study drug for subjects that terminate study
participation early). See Section 12 and Table 12-1 for the
Schedule of Events and description of the study
procedures.
Criteria for Evaluation
Variables:
Pharmacodynamic:
Pharmacodynamic variables will include
electroretinography (ERG) rod b-wave amplitudes and the
degree of suppression of the b-wave rod recovery after a
photobleaching light.
Safety:
Safety variables will include adverse events (AEs), BCVA,
slit-lamp biomicroscopy, intraocular pressure (IOP),
dilated ophthalmoscopy, physical examination findings,
vital signs, electrocardiograms (ECGs), and clinical
laboratory tests.
Study Endpoints
Pharmacodynamic:
The degree of suppression compared to baseline of the rod
b-wave amplitudes after a photobleaching light.
Safety:
Safety endpoints will include:
1. Incidence, severity, and seriousness of AEs, and
discontinuations due to AEs.
2. Change from baseline in laboratory values, vital
signs, physical examination findings, ECGs, and
ophthalmic assessments.


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Statistical Analyses:
This study will enroll approximately 30 subjects with a
goal of having 24 subjects (8 per treatment arm) complete
the masked treatment phase of the study.  This sample size
is not based on statistical rationale but is considered
adequate to determine the PD response of each dose of
emixustat in this study population.
Pharmacodynamic variables will include ERG rod b-wave
amplitudes and the degree of suppression of the rod b-
wave rod recovery after a photobleaching light.  The
degree of suppression will be determined as the percent
decrease from baseline to post-treatment in the rate of
recovery of the rod b-wave amplitude during the 30-
minute post-bleaching period.  Results will be summarized
by treatment arm.
Safety and tolerability will be assessed on the basis of
ocular and non-ocular AEs, serious adverse events (SAEs),
ophthalmic examination findings, vital signs, physical
examination findings, ECG findings, and laboratory
analyses.  Safety assessments will be summarized
descriptively.
Study Duration:
The dosing period is 1 month, and subjects will complete
the study approximately 1 month after taking the last dose
of study drug.


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4
TABLE OF CONTENTS
1
Sponsor Signature Page..........................................................................2
2
Key Roles and Contacts .........................................................................3
3
Protocol Summary..................................................................................4
4
TABLE OF CONTENTS.....................................................................10
LIST OF IN-TEXT TABLES .......................................................................13
LIST OF IN-TEXT FIGURES......................................................................13
5
Glossary of Abbreviations and Definition of Terms............................14
6
Introduction..........................................................................................16
6.1
Background .......................................................................................................16
6.2
Rationale for the Study......................................................................................16
6.3
Rationale for Dose Selection.............................................................................18
7
Study Objectives ..................................................................................19
7.1
Primary Objective..............................................................................................19
7.2
Secondary Objectives........................................................................................19
8
Investigational Plan..............................................................................19
8.1
Overall Study Design and Plan .........................................................................19
8.2
Number of Subjects...........................................................................................21
8.3
Study Sites.........................................................................................................21
8.4
Discussion of Study Design, Including the Choice of Control Groups.............21
8.5
Pharmacodynamic Variables.............................................................................21
8.6
Safety Variables ................................................................................................21
9
Study Population ..................................................................................21
9.1
Target Population ..............................................................................................21
9.2
Inclusion Criteria...............................................................................................21
9.3
Exclusion Criteria..............................................................................................22
9.4
Determination of Study Eye..............................................................................24
9.5
Enrollment and Subject Identification Numbers...............................................24
9.6
Subject Withdrawal from Treatment or Study ..................................................25
9.7
End of Study......................................................................................................26


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10
Randomization and Masking................................................................26
10.1
Randomization...................................................................................................26
10.2
Masking.............................................................................................................26
11
Study Treatments..................................................................................27
11.1
Drug Dosage and Administration......................................................................27
11.2
Supply, Packaging, Labeling, and Storage........................................................27
11.3
Measurement of Study Drug Adherence...........................................................28
11.4
Study Drug Accountability................................................................................28
11.5
Prior and Concomitant Therapy ........................................................................28
12
Study Visits ..........................................................................................30
12.1
Early Termination..............................................................................................33
12.2
Unscheduled Visits............................................................................................33
13
Study Assessments...............................................................................33
13.1
Informed Consent..............................................................................................33
13.2
Eligibility Assessment.......................................................................................33
13.3
Demographic Data.............................................................................................34
13.4
Medical, Surgical, and Ocular History..............................................................34
13.5
Prior and Concomitant Therapy ........................................................................34
13.6
Abbreviated Physical Examinations..................................................................34
13.7
Vital Signs.........................................................................................................34
13.8
12-Lead Electrocardiogram...............................................................................34
13.9
Pregnancy Testing.............................................................................................34
13.10
Clinical Laboratory Evaluations........................................................................35
13.11
ABCA4 Genotype Testing ................................................................................35
13.12
Visual Acuity.....................................................................................................36
13.13
Slit-lamp Biomicroscopy...................................................................................36
13.14
Intraocular Pressure...........................................................................................36
13.15
Dilated Ophthalmoscopy...................................................................................37
13.16
Electroretinography...........................................................................................37
13.17
Reduced-illuminance Fundus Autofluorescence...............................................37
13.18
Evaluation of Adverse Events...........................................................................38


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14
Data Monitoring Committee ................................................................43
15
Study Endpoints ...................................................................................43
15.1
Pharmacodynamic Endpoint..............................................................................43
15.2
Safety Endpoints................................................................................................43
16
Statistical Analysis and Study Variables .............................................43
16.1
Determination of Sample Size...........................................................................43
16.2
Data Sets to be Analyzed...................................................................................43
16.3
Subject Disposition............................................................................................44
16.4
Analysis of Demographic and Baseline Data....................................................44
16.5
Compliance and Exposure.................................................................................44
16.6
Pharmacodynamic Analysis ..............................................................................44
16.7
Safety Analysis..................................................................................................45
16.8
Subgroup Analysis ............................................................................................45
16.9
Interim Analyses................................................................................................45
17
Data Handling and Quality Assurance.................................................46
17.1
Case Report Forms............................................................................................46
17.2
Monitoring of the Study ....................................................................................46
17.3
Inspection of Records........................................................................................46
17.4
Study Record Retention.....................................................................................47
18
Study Ethical Considerations...............................................................47
18.1
Ethical Conduct of the Study.............................................................................47
18.2
Informed Consent..............................................................................................48
18.3
Institutional Review Board................................................................................48
19
Administrative Considerations.............................................................49
19.1
Confidentiality...................................................................................................49
19.2
Modification of the Protocol .............................................................................49
19.3
Protocol Deviations...........................................................................................50
19.4
Study Reporting Requirements .........................................................................50
19.5
Financial Disclosure..........................................................................................50
19.6
Financial Obligations ........................................................................................51
19.7
Investigator Documentation ..............................................................................51


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19.8
Clinical Trial Agreement...................................................................................51
19.9
Policy for Publication and Presentation of Data ...............................................52
20
Investigator Agreement........................................................................53
21
References............................................................................................54
22
Appendices...........................................................................................55
22.1
Appendix A:  Summary of Changes for Amendments......................................56
LIST OF IN-TEXT TABLES
Table 11-1:  Prohibited CYP2D6 Inhibitors and Inducers.................................................29
Table 12-1:  Schedule of Events........................................................................................31
Table 13-1:  Clinical Laboratory Assessments Performed During the Study....................35
LIST OF IN-TEXT FIGURES
Figure 1:  Overview of the Visual Cycle and Modulation by Emixustat...........................17
Figure 2:  Emixustat Reduces Lipofuscin Autofluorescence and A2E in ABCA4-/-
Mice ...............................................................................................18
Figure 3:  Study Design Schema........................................................................................20


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5
Glossary of Abbreviations and Definition of Terms
ABBREVIATION
DEFINITION
11cRDH
11-cis-retinol dehydrogenase
A2E
N-retinylidene-N-retinylethanolamine
ABCA4
ATP binding cassette subfamily A member 4
AE
adverse event
ALT
alanine aminotransferase
AMD
age-related macular degeneration
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AtRDH
all-trans-retinal dehydrogenase
BCVA
best-corrected visual acuity
CFR
Code of Federal Regulations
CRA
clinical research associate
CTCAE
common terminology criteria for adverse events
CYP
cytochrome P450 (eg, CYP2D6)
ECG
electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
ERG
electroretinography
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FAF
fundus autofluorescence
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Council for Harmonisation
ID
identification
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
IWRS
interactive web response system
LRAT
lecithin retinol acyl transferase
MA
macular atrophy
MedDRA
Medical Dictionary for Regulatory Activities
msec
milliseconds
ONL
outer nuclear layer
PD
pharmacodynamics


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ABBREVIATION
DEFINITION
QD
once daily
RPE
retinal pigment epithelium
RPE65
retinal pigment epithelium 65
SA
Safety Analyses (set of subjects)
SAE
serious adverse event
STGD
Stargardt disease
STGD1
autosomal recessive STGD
ULN
upper limit of the normal range


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6
Introduction
6.1
Background
Emixustat hydrochloride (emixustat) is under clinical development by Acucela Inc. (Acucela)
for retinal diseases including Stargardt disease (STGD).
Stargardt disease is a rare, inherited, degenerative disease of the retina affecting approximately
1 in 8,000 to 10,000 individuals and is the most common type of hereditary macular
dystrophy.1 There are no approved treatments for STGD.
Stargardt disease is characterized by an excessive build-up of lipofuscin at the level of the
retinal pigment epithelium (RPE).  Lipofuscin, which normally accumulates with age, consists
of lipids, proteins, and toxic bis-retinoids such as N-retinylidene-N-retinylethanolamine (A2E)
that are mainly derived from incompletely digested photoreceptor outer segments.
Accumulation of the toxic bis-retinoids found in lipofuscin is thought to cause RPE cell
dysfunction and eventual apoptosis, which leads to photoreceptor death and loss of vision.
While there are multiple sub-types of STGD, autosomal recessive STGD (STGD1) represents
the vast majority (> 95%) of all cases. Autosomal recessive STGD is typically diagnosed in
the first three decades of life and is caused by mutations of the adenosine triphosphate (ATP)
binding cassette subfamily A member 4 (ABCA4) gene.2 The ABCA4 gene product transports
N-retinylidene-phosphatidylethanoloamine (a precursor of toxic bis-retinoids consisting of one
molecule of phosphatidylethanolamine covalently bound to one molecule of 11-cis- or all-
trans-retinal) from the lumen side of photoreceptor disc membranes to the cytoplasmic side,
where the retinal is hydrolyzed from phosphatidylethanolamine.3 Mutations of the ABCA4
gene result in accumulation of this precursor in disc membranes that are eventually
phagocytized by RPE cells, where the precursors are converted into toxic bis-retinoids such as
A2E.  In addition to being a precursor to A2E, all-trans-retinal has also been implicated in the
pathogenesis of STGD through its role in light-mediated toxicity.4
6.2
Rationale for the Study
The target for emixustat is the visual cycle isomerohydrolase, retinal pigment epithelium 65
(RPE65). As depicted in Figure 1, enzymatic processing within the visual cycle begins with
delivery of vitamin A (all-trans-retinol) from the blood circulation as a ternary complex bound
to retinol binding protein and transthyretin. Upon entry into the RPE, all-trans-retinol is
converted to a retinyl ester through the activity of lecithin retinol acyl transferase (LRAT).
The resulting all-trans-retinyl esters represent a storage form of vitamin A upon which RPE65
acts. Following conversion to 11-cis-retinol, an 11-cis-retinol dehydrogenase (11cRDH)
catalyzes the formation of the visual chromophore, 11-cis-retinal. The visual chromophore is


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then delivered to rod and cone outer segments where it combines with opsins to form visual
pigments (eg, rhodopsin). Light activation of rhodopsin initiates the process of visual
transduction and liberates all-trans-retinal as a photoproduct. Reduction of all-trans-retinal,
via all-trans-retinal dehydrogenase (AtRDH), produces all-trans-retinol which is transferred
back to the RPE for recycling within the RPE.
Figure 1: Overview of the Visual Cycle and Modulation by Emixustat
Emixustat is a potent inhibitor of RPE65 isomerization activity and reduces the production of
visual chromophore (11-cis-retinal) in a dose-dependent and reversible manner. Because
11-cis-retinal and its photoproduct (all-trans-retinal) are substrates for biosynthesis of retinoid
toxins (eg, A2E), chronic treatment with emixustat retards the rate at which these toxins
accumulate. In an animal model of STGD1 (ABCA4-/- mice) in which excessive A2E
accumulates, chronic treatment (3 months, starting at 2 months of age) with emixustat doses
≥0.3 mg/kg/day produced statistically significant reductions in A2E accumulation, compared
to vehicle-treated mice (Figure 2).
  These data
suggest that the accumulation of A2E can be reversed by emixustat treatment.5, 6


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Figure 2:  Emixustat Reduces Lipofuscin Autofluorescence and A2E in ABCA4-/- Mice
All-trans-retinal is known to be a key mediator of light damage. In wild-type mice, prolonged
exposure to intense white light (8,000 lux for 1 hour) causes repeated photobleaching of
11-cis-retinal to all-trans-retinal which results in near complete destruction of the outer nuclear
layer (ONL) of the retina. The ability of emixustat to rapidly and potently reduce the
production of 11-cis-retinal, and thus all-trans-retinal, affords protection from light damage. In
a mouse light toxicity model, pre-treatment with a single dose of emixustat (1.0 or 3.0 mg/kg)
has been shown to provide near complete preservation of the ONL, compared to vehicle-
treated mice (p<0.01, ED50 = 0.20 mg/kg).
These nonclinical findings suggest that, by decreasing the availability of 11-cis-retinal and thus
all-trans-retinal, orally administered emixustat may slow the progression of STGD by reducing
retinal pathology caused by prominent cellular stressors such as toxic retinoid by-products and
light.
6.3
Rationale for Dose Selection
To characterize the pharmacodynamics (PD) of emixustat in subjects with macular atrophy
(MA) secondary to STGD, doses within the range previously assessed for safety in subjects


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with geographic atrophy secondary to age-related macular degeneration (AMD) have been
selected.
A once-daily schedule for administration of emixustat has been chosen for this study based on
the pharmacokinetic profile characterized in the Phase 1 program. Following multiple dosing
in healthy subjects who received doses ranging from 5 to 40 mg of emixustat once daily (QD)
for 14 days, emixustat was steadily eliminated with terminal elimination half-life values
ranging from 4.6 to 7.9 hours. Pharmacokinetic values were similar on Days 1 and 14, with
mean accumulation ratio for area under the concentration curve values ranging from 1.04 to
1.19 across all treatments, indicating no accumulation following QD dosing with emixustat for
14 days.7
7
Study Objectives
7.1
Primary Objective
The primary objective of this study is to characterize the PD of emixustat in subjects with MA
secondary to STGD.
7.2
Secondary Objectives
The secondary objective of this study is to evaluate the safety and tolerability of emixustat
when administered orally for 1 month.
8
Investigational Plan
8.1
Overall Study Design and Plan
This is a multicenter, randomized, masked study to characterize the PD and safety and
tolerability of emixustat in subjects with MA secondary to STGD. Subjects will be randomly
assigned to 1 of 3 treatment arms in a 1:1:1 ratio.  Treatment arms include:

Emixustat 2.5 mg

Emixustat 5 mg

Emixustat 10 mg
Subjects will self-administer study drug QD in the evening for 1 month, from the evening of
the Baseline visit through the evening before the End of Treatment visit.


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The scheduled visits include Screening (within 30 days prior to Baseline), Baseline (Day 1),
and End of Treatment (Month 1). A Study Exit visit will be performed 30 days after the End
of Treatment visit (30 days after the last dose of study drug for subjects that terminate study
participation early).
The study design is presented schematically in Figure 3.
Figure 3: Study Design Schema


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8.2
Number of Subjects
Approximately 30 subjects across multiple clinical sites will be enrolled (approximately 10
subjects per treatment arm) in order to obtain approximately 8 evaluable subjects per arm.
8.3
Study Sites
This study will be conducted at 4 to 6 clinical sites in the United States.
8.4
Discussion of Study Design, Including the Choice of Control Groups
Randomization and masking will be used to minimize bias in subject selection and the
evaluation of subjects during the study.
Doses within the range previously assessed for safety in subjects with GA secondary to AMD
have been selected, and a QD dosing regimen is based on the pharmacokinetic profile
characterized in the Phase 1 program.7
The 1-month dosing period and sample size are expected to provide the opportunity to
determine the PD response of each dose of emixustat and to evaluate safety and tolerability.
8.5
Pharmacodynamic Variables
Pharmacodynamic variables will include electroretinography (ERG) rod b-wave amplitudes
and the degree of suppression of the b-wave rod recovery after a photobleaching light.
8.6
Safety Variables
Safety variables will include adverse events (AEs), best-corrected visual acuity (BCVA), slit-
lamp biomicroscopy, intraocular pressure (IOP), dilated ophthalmoscopy, physical examination
findings, vital signs, electrocardiograms (ECGs), and clinical laboratory tests. Pregnancy tests
will be conducted for women of childbearing potential.
9
Study Population
9.1
Target Population
The target population of this study is male or female subjects ≥18 years of age who have MA
secondary to STGD.
9.2
Inclusion Criteria
Subjects who meet all of the following criteria at Screening and Baseline (unless otherwise
indicated) may be eligible for inclusion in the study:


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1. Males or females, age ≥18 years.
2. Clinical diagnosis of MA secondary to STGD in one or both eyes as determined by the
Investigator and confirmed by the central image reading center.
3. At least 2 pathogenic mutations of the ABCA4 gene.  If only one ABCA4 allele has a
pathogenic mutation, the subject must have a typical STGD phenotype (ie, at least one
eye has flecks at the level of the RPE typically seen in STGD) and be approved for
enrollment by the Sponsor.
4. Total area of MA (definitely decreased autofluorescence plus questionably decreased
autofluorescence) in the study eye equal to 1.25 - 26 mm2 (~0.5 – 10.25 disc areas) in
size as determined by the central image reading center’s assessment of fundus
autofluorescence (FAF) imaging at Screening.
5. The entire lesion must be completely visualized on the macula-centered image
(Field 2 - Macula Image).
6. Early Treatment Diabetic Retinopathy Study BCVA of ≥20 letters (approximately
≥20/400 Snellen) in the study eye.
7. Adequate clarity of ocular media and adequate pupillary dilation to permit good quality
imaging of MA in the study eye as determined by the Investigator.
8. Able and willing to provide written informed consent before undergoing any study-
related procedures.
9. Able to reliably administer oral medication by self or with available assistance.
9.3
Exclusion Criteria
Subjects will be excluded from participation in the study if they meet any of the following
criteria at Screening or Baseline (unless otherwise indicated):
1. Macular atrophy associated with a condition other than STGD in either eye.
2. Presence in either eye of an active ocular disease that in the opinion of the Investigator
compromises or confounds visual function, including, but not limited to, choroidal
neovascularization, diabetic retinopathy, uveitis, other macular diseases, or
uncontrolled glaucoma/ocular hypertension.
3. History of any intraocular or ocular surface surgery in either eye within 3 months of
Screening.


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4. Current or previous participation in an interventional study to treat STGD using gene
therapy or stem cell therapy at any time, or participation in an interventional study of a
vitamin A derivative ≤3 months prior to screening.
5. Known serious hypersensitivity to emixustat or any of the excipients in emixustat
tablets (ie, silicified microcrystalline cellulose, pregelatinized starch, colloidal silicon
dioxide, and stearic acid).
6. Prohibited medications:  Systemic use of a strong inducer of, or a strong or moderate
inhibitor of, cytochrome P450 2D6 (CYP2D6) beginning within 4 weeks prior to
Screening or between Screening and Baseline, or planned use during the study period.
7. Any of the following laboratory abnormalities at Screening:
a.
Aspartate transaminase (AST)/alanine transaminase (ALT) > 2.5 × upper limit of
normal (ULN).
b. Total bilirubin > 1.5 × ULN.
c.
Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2.
d. Impaired hematologic function:  hemoglobin < 10 g/dL; neutrophil count < 1.6 ×
109/L; or platelet count < 100 × 109/L.
Any laboratory screening test that meets the abnormality criteria stated above can be
repeated once within the 30-day period from Screening to Baseline.
8. Participation in any study using an investigational drug within 5 half-lives (of the
investigational drug) of Screening, or, if the half-life is not known, within 30 days of
Screening.
9. Participation in any study of an investigational device within 60 days of Screening.
10. Anticipated participation during the study period in any other study using an
investigational study drug or interventional device.
11. Presence of other medical or ophthalmic disease, physical examination finding, or
clinical laboratory finding that in the opinion of the Investigator contraindicates the use
of an investigational drug; places the subject at risk by participating in the study; might
interfere with the evaluation of the PD or safety of emixustat; negatively impacts
subject compliance with the protocol; confounds the ability to interpret data from the
study; or jeopardizes the subject’s ability to complete the protocol.
12. Current or history of cancer (except for adequately treated basal cell or squamous cell
carcinoma of the skin) within 1 year of Screening.


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13. History of myocardial infarction, stroke, unstable ischemic heart disease, uncontrolled
cardiac arrhythmia, or hospitalization for congestive heart failure within 6 months of
Screening.
14. Anticipated hospitalization for a medical/surgical procedure(s) that could result in
interruption/premature cessation of study treatment or participation.
15. Electrocardiogram with a clinically significant abnormal finding (eg, acute ischemia,
bundle branch block) or a QT interval, corrected for heart rate by Bazett’s formula
(QTcB) or Fridericia’s formula (QTcF), of > 460 milliseconds (msec) for men and
> 470 msec for women at Screening.
16. Female subjects who are pregnant or lactating.
17. Female subjects of childbearing potential (ie, not postmenopausal for at least 2 years
and not surgically sterile) who are not willing to practice a medically accepted method
of birth control with their non-surgically sterile male sexual partner from Screening
through 30 days after the final dose of study drug.  Medically accepted methods of birth
control include abstinence, hormonal contraceptives, nonhormonal intrauterine
contraceptive device with spermicide, condom with spermicide, contraceptive sponge
with spermicide, diaphragm with spermicide, or cervical cap with spermicide.
18. Male subjects who are not surgically sterile and are not willing to practice a medically
accepted method of birth control with their female partner of childbearing potential (as
listed above) from Screening through 30 days after the final dose of study drug.
9.4
Determination of Study Eye
The study eye will be determined as the eye that meets all of the inclusion criteria and none of
the exclusion criteria.  If both eyes qualify, the eye with the larger MA lesion area will be
selected as the study eye.  If both eyes qualify and are equal in MA lesion area, the right eye
will be selected as the study eye.  The study eye will be determined by the Investigator; MA
lesion characteristics will be confirmed by the central image reading center.
9.5
Enrollment and Subject Identification Numbers
All subjects screened for the study who sign an informed consent form (ICF) will be assigned a
screening number that will be entered in the Screening and Enrollment Log. The screening
number will be the subject identification (ID) number for the remainder of the study.


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9.6
Subject Withdrawal from Treatment or Study
Subjects may withdraw from treatment or the study for any reason and at any time.  Subjects
may also be removed from study for any of the following circumstances:

Adverse events

Investigator/Sponsor decision to withdraw subject from study

Subject withdrawal of consent

Pregnancy

Lost to follow-up

Death

Study termination by Sponsor

Other
All subjects who discontinue treatment prematurely will be withdrawn from the study.
Handling of Withdrawals
At the time of withdrawal, the Investigator should advise the subject of the other available
options.  When a subject is withdrawn from the study for any reason, the primary reason for
withdrawal will be recorded in the electronic case report form (eCRF).  For any subject who
withdraws due to an AE, the reason for withdrawal must only be recorded as an AE (no other
reason may be recorded). All subjects who withdraw from the study prematurely during the
masked treatment phase will undergo assessments listed for the Early Termination visit and
then complete the Study Exit visit 30 days following the last dose of study drug.
A subject who fails to return for any scheduled visit will be contacted by the site personnel in
an attempt to have the subject comply with the protocol.  After randomization, if a subject
cannot be contacted with 3 telephone calls over a period of 2 weeks followed by a certified
letter and there is no known reason for discontinuation (eg, withdrawn consent or AE), the
reason for discontinuation will be recorded as “lost to follow-up.” The date the certified letter
was mailed will be considered the date of study withdrawal.
In the event of a subject death during the study, the date of death (as listed on the death
certificate) will be used as the date of study withdrawal. It is vital to obtain follow-up data on
any subject who is withdrawn because of an AE.  In any case, every effort must be made to
undertake protocol-specified safety follow-up procedures.
The Medical Monitor should be notified promptly when a subject is withdrawn.


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Replacements
Subjects who are withdrawn from the study will not be replaced.
Sponsor or Regulatory Agency Termination of the Study
Although the Sponsor intends to complete the study, the right is reserved to discontinue the
study at any time for clinical or administrative reasons, or if required by the local regulatory
authority.
9.7
End of Study
The end of study will be defined as the date of the last visit of the last subject.  A summary of
the End of Study report will be sent to Institutional Review Boards (IRBs), if required, within
12 months of the end of the study.
10 Randomization and Masking
10.1
Randomization
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase
the likelihood that known and unknown subject attributes (eg, demographics and baseline
characteristics) are evenly balanced across treatment groups, and to enhance the validity of
statistical comparisons.  Once a subject meets all qualification criteria at Screening and
Baseline, they will be enrolled and randomly assigned in a masked fashion to study treatment
through the use of an interactive web response system (IWRS).
At Baseline (Day 1), eligible subjects will be randomized in a 1:1:1 ratio to 1 of 3 treatment
arms:

Emixustat 2.5 mg

Emixustat 5 mg

Emixustat 10 mg
Subjects will receive a randomization number when randomized at Baseline.
10.2
Masking
Study subjects and Investigators and their staff will be masked to the identity of treatment until
after the final database is locked. For ERG recordings, the technician performing the ERG
must ensure that the recordings will be filed and maintained in a masked fashion and will not
be allowed to perform any functional assessments or assess AEs.  To ensure masking, site


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personnel who perform any functional assessments and/or assess AEs will not be allowed to be
involved in the ERG procedure and will not be allowed access to ERG results.
The 3 dosage strengths of emixustat will be identical-appearing tablets, and each treatment will
be packaged in identical, tamper-proof, blister packaging to maintain masking.
Appropriate precautions must be taken to prevent unauthorized access to the randomization
scheme. The decision to unmask a subject’s treatment assignment is to be made by the
Investigator only if the subject’s safety requires it. The treatment assignment for an individual
subject may be obtained through the IWRS only in the case of a medical emergency when
identity of the treatment assignment is essential for the clinical management of the subject.
The Investigator must make every effort to contact the Medical Monitor before unmasking the
treatment assignment. If unmasking is required for emergency subject management, the
Investigator must document the medical rationale for unmasking and forward the information
to the Sponsor within 24 hours of unmasking without revealing to the Sponsor personnel the
treatment assignment. If emergency unmasking is required for any reason, the subject will be
withdrawn from the study.
11 Study Treatments
11.1
Drug Dosage and Administration
Subjects will take 1 tablet (2.5, 5, or 10 mg) of emixustat orally QD in the evening for 1 month,
from the evening of randomization until the evening before the End of Treatment (Month 1)
visit. Subjects will be maintained on the randomized dose for the entire dosing period.
11.2
Supply, Packaging, Labeling, and Storage
Study drug (emixustat) will be packaged in tamper proof, blister packaging with identical
labeling, except for the kit number.  All study site personnel will remain masked to treatment
assignment in order to allow for an unbiased assessment of study measures.  The treatment
assignments will remain masked until database lock and authorization of data release by the
Sponsor according to standard operating procedures.
Each kit will be labeled with a single panel label clearly displaying a space for the subject ID
number (to be filled in by the clinical site at the time the kit is dispensed to the subject), kit
number, protocol number, contents, storage conditions, Sponsor’s name and address,
instructions for use, and appropriate precautionary statements.


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Study drug will be stored at ambient room temperature in a securely locked cabinet or
enclosure.  Access should be strictly limited to the Investigators and their designees. Neither
the Investigators nor any designees may provide study drug to any individual not participating
in this protocol. Study drug will be dispensed by site personnel following randomization at the
Baseline visit. Subjects will be instructed to store study drug at room temperature under secure
conditions.
11.3
Measurement of Study Drug Adherence
Study drug will be administered orally QD in the evening for 1 month.  At the End of
Treatment (Month 1) visit, the subject will be queried regarding compliance with the treatment
regimen. In addition, site personnel will collect the used blister pack of study drug and review
subject compliance.
11.4
Study Drug Accountability
The Investigator will maintain accurate records of inventory and dates of receipt of all study
drug.  In addition, accurate records will be kept regarding when and how much study drug is
dispensed to each subject and how much is returned by each subject.  Reasons for departure
from the expected dispensing regimen must also be recorded.
For regulatory requirements regarding drug accountability, all unused study drug and opened,
empty blister packaging from used study drug will be reconciled by the clinical research
associate (CRA).  Once reconciled, study drug (both used and unused) will be returned to the
Sponsor or designee according to applicable state and federal regulations.
Study drug returned by the site must be accompanied by appropriate documentation and be
clearly identified by protocol number and study site on the outermost shipping container.
Returned supplies should be in the original containers (eg, subject kits).  The CRA should
facilitate the return of unused study drug and opened, empty blister packaging from used study
drug.
11.5
Prior and Concomitant Therapy
In addition to the exclusion criteria, the medications listed in Table 11-1 are the systemic
CYP2D6 inhibitors and inducers that are prohibited during the study or within 4 weeks prior to
Screening.


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Table 11-1: Prohibited CYP2D6 Inhibitors and Inducers
Prohibited CYP2D6 Inhibitors and Inducers
Inhibitors:

Amiodarone

Cinacalcet

Terbinafine

Quinidine

Bupropion

Duloxetine

Fluoxetine

Paroxetine

Sertraline
Inducers: No medications currently meet this criterion
If elective, urgent, or emergency surgery is required at any time between randomization and
End of Treatment (Month 1), the investigator will confer with the Medical Monitor, who will
determine if a temporary discontinuation of masked study drug is warranted before and/or after
the surgery.
For subjects who undergo ocular treatments, procedures, or surgeries (eg, retinal detachment
surgery) with the potential to affect protocol assessments or disease outcomes, the Investigator
should confer with the Medical Monitor to determine whether or not the subject should
continue with study drug.
The Medical Monitor should be notified before prohibited medication or therapy (as listed in
Section 9.3 Exclusion Criteria and in Table 11-1) is administered unless the safety of the
subject requires immediate action. The decision to administer a prohibited medication or
therapy should be done with the safety of the subject as the primary consideration. The
Medical Monitor will determine whether or not the subject may continue with study
participation. The Investigator should contact the Medical Monitor if permissibility of a
specific medication or therapy is in question to discuss whether or not the subject should
continue with study participation.


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12 Study Visits
The Schedule of Events is presented in Table 12-1.
The scheduled visits include Screening (within 30 days prior to Baseline), Baseline (Day 1),
and End of Treatment (Month 1). A Study Exit visit will be performed 30 days after the End
of Treatment (Month 1) visit (30 days after the last dose of study drug for subjects that
terminate study participation early).
All required ophthalmic exams should be performed on both eyes at each study time point. For
each visit, all ophthalmic exams must be performed on the same day and cannot be split
between 2 or more days. Best-corrected visual acuity must be completed prior to any
ophthalmic exam requiring contact with the eye. Fundus autofluorescence must be performed
prior to IOP measurement if IOP is to be assessed using Goldmann tonometry.




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c If the subject terminates early during the masked treatment phase, these evaluations should be performed at the time that study drug is stopped
or as soon as possible after stopping study drug.
d Study day is based on 30 days = 1 month.
e If the subject is not dosed by Day 30 of the 30-day screening period, the subject may be re-screened by repeating all of the screening
procedures.
f Review of the inclusion/exclusion criteria at Baseline must include confirmation of eligibility assessment from the central image reading
center.
g Height will only be recorded at the Screening visit.
h Pregnancy test for women of childbearing potential will be via serum at Screening and via urine at all other visits.
i Any laboratory screening tests that meets the abnormality criteria stated in the exclusion criteria can be repeated once within the 30-day period
from Screening to Baseline.
j Only perform if safety laboratory test results at the Month 1 or Early Termination visit were considered clinically significant by the
Investigator.
k ABCA4 genotyping will be performed unless the subject’s ABCA4 genotype is already documented.
l All required ophthalmic exams should be performed on both eyes at each study time point. For each visit, all ophthalmic exams must be
performed on the same day and cannot be split among 2 or more days. Best-corrected visual acuity must be completed prior to any ophthalmic
exam requiring contact with the eye.
m The site will attempt to collect IOP measurements at approximately the same time of day for a given subject. Intraocular pressure using
Goldmann tonometry must be performed after FAF.


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12.1
Early Termination
Subjects who discontinue from the study during the masked treatment phase will undergo an
Early Termination visit when study drug is stopped, or as soon as possible after stopping study
drug; they will then undergo Study Exit visit evaluations 30 days after the last study drug dose.
If the Early Termination visit occurs ≥25 days after last study drug dose, the Early
Termination and Study Exit visits may be combined.
12.2
Unscheduled Visits
Unscheduled visits may be necessary due to AEs or for other reasons. The Investigator may
examine a subject as often as is medically necessary while the subject is enrolled in the study.
In addition, if the Investigator believes follow-up is needed after the Study Exit or Early
Termination visit, it should occur as an unscheduled visit at his/her discretion. Assessments
performed at unscheduled visits are at the discretion of the Investigator.
13 Study Assessments
This section describes the study assessment procedures.  For timing of study assessments,
see the Schedule of Events (Table 12-1).
13.1
Informed Consent
At Screening, clinical sites will obtain a signed ICF from each subject prior to performing any
study-related procedures (including any pre-treatment procedures or withdrawal from
exclusionary medications). Informed consent must be obtained and documented in the
subject’s chart prior to initiation of any procedures that are performed solely for the purpose of
determining eligibility for research.
13.2
Eligibility Assessment
At Screening, each inclusion and exclusion criterion must be checked and documented for each
subject, and restricted and prohibited prior and concomitant therapy must be assessed and
documented. Results of eligibility assessment from the central image reading center must be
present prior to randomization.
At Baseline, eligibility requirements must be reviewed to determine if the subject is eligible to
continue in the study.


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13.3
Demographic Data
Demographic data, including age, sex, race, ethnicity, and iris color, will be collected at the
Screening visit.
13.4
Medical, Surgical, and Ocular History
A medical, surgical, and ocular history should be obtained from each subject at Screening and
updated at Baseline, and any time the Investigator learns of information that should be included
in the subject’s medical, surgical, or ocular history.
13.5
Prior and Concomitant Therapy
All current therapies and relevant prior therapies will be assessed at Screening and updated at
Baseline.  Concomitant therapies will be collected and recorded throughout the study.
13.6
Abbreviated Physical Examinations
The abbreviated physical examination will be performed by qualified study personnel.  This
will consist of a review of body systems and examination of the heart and lungs with a
stethoscope. Based upon medical history and findings from the above portions of the exam,
more detailed examinations of additional systems may be indicated including: skin,
ears/nose/throat, abdomen, extremities, neurological system, and “other.” Height will only be
recorded at the Screening Visit. All abnormal findings will be recorded.
13.7
Vital Signs
Vital signs (systolic and diastolic blood pressure, pulse, and respiratory rate) will be assessed
by qualified study personnel after the subject has been resting in a sitting or supine position for
at least 5 minutes.
13.8
12-Lead Electrocardiogram
Safety 12-lead ECGs will be obtained by qualified study personnel with the subject in a supine
position after resting for at least 3 minutes.  Electrocardiograms will be read by the Investigator
or other qualified designee.
13.9
Pregnancy Testing
A serum pregnancy test will be conducted at the Screening visit, and a urine pregnancy test
will be conducted at all other visits for women of childbearing potential.


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13.10 Clinical Laboratory Evaluations
The laboratory assessments listed in Table 13-1 are to be performed according to the Schedule
of Events (Table 12-1).
The investigator must review the laboratory results, document this review, and record any
clinically significant changes occurring during the study on the AE eCRF.  All laboratory
results must be reviewed promptly to evaluate the subject’s safety. Prior to randomization,
results must be present and evaluable for laboratory parameters associated with an exclusion
criterion. With the exception of the urine pregnancy test, all laboratory assessments will be
performed by a central laboratory.
Table 13-1: Clinical Laboratory Assessments Performed During the Study
Category
Parameters
Chemistry (serum)
Sodium, potassium, chloride, glucose, blood urea nitrogen,
creatinine, calcium, phosphorus, total protein, albumin, ALT,
AST, total bilirubin, alkaline phosphatase, creatine
phosphokinase, cholesterol, and triglycerides, uric acid, and
eGFR (by the Modification of Diet in Renal Disease Study
equation)
Hematology
Hematocrit, hemoglobin, red blood cell count, platelet count,
and white blood cell count with automated differential (% and
absolute count)
Pregnancy a (serum at
Screening, urine at all
other clinic visits)
ß-human chorionic gonadotropin
a Women of childbearing potential only
13.11 ABCA4 Genotype Testing
ABCA4 genotyping will be performed at Screening by a central laboratory unless the subject’s
ABCA4 genotype is already documented.
If only one ABCA4 allele has a pathogenic mutation, the subject must have a typical STGD
phenotype (ie, at least one eye has flecks at the level of the RPE typically seen in STGD) and
be approved for enrollment by the Sponsor.


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13.12 Visual Acuity
Total BCVA letter score will be measured using the Early Treatment Diabetic Retinopathy
Study (ETDRS) retro-illuminated chart, the ETDRS electronic visual acuity (ETDRS-EVA)
system, or the standard ETDRS wall chart in normal luminance lighting. Total BCVA letter
score will be recorded as total letter score in each eye.
Visual acuity testing should precede any examination requiring contact with the eye.  In order
to provide standardization and well-controlled assessments of BCVA during the study, all
BCVA assessments at a single site must be consistently done using the same lighting
conditions during the entire study.  The Investigator should also consistently use the same
correction, chart type, and measurement procedure for an individual subject during the entire
study.
13.13 Slit-lamp Biomicroscopy
Slit-lamp biomicroscopy will be performed for each eye prior to dilating the pupil.
Magnification will be consistent with standard clinical practice.  The subject will be seated
during the examination.  This procedure should be conducted in the same manner for all
subjects and will include an assessment of each of the following as normal or abnormal:

Eyelids

Conjunctiva

Cornea

Anterior chamber

Iris

Lens
All abnormal findings will be recorded.
13.14 Intraocular Pressure
Intraocular pressure will be measured in each eye and results will be recorded in mm Hg.
At visits where IOP is to be measured, a single measurement will be made.  Contact or non-
contact tonometry can be performed.  The same tonometry method should be used throughout
the study.


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The tonometer must be calibrated for accuracy before the first subject in the study undergoes
the first examination and according to manufacturer specifications during the study, until the
last subject has exited the study.
The site will attempt to collect IOP measurements at approximately the same time of day for a
given subject. If IOP is measured using a Goldmann tonometer, it must be performed after
FAF.
13.15 Dilated Ophthalmoscopy
A dilated fundus examination will be performed for each eye in all subjects.  The following
will be observed for the presence of abnormalities:

Vitreous

Peripheral retina

Macula

Choroid

Optic nerve
All abnormal findings will be recorded.
13.16 Electroretinography
Full-field electroretinography will be performed for each eye in all subjects.
Electroretinography data will be sent to the central ERG reading center to be evaluated.
Electroretinography will be performed per the ERG manual.  Briefly, the ERG procedure will
begin with the subject’s pupils being maximally dilated, followed by a period of dark
adaptation that lasts for at least 30 minutes.  At the end of this period, an electrode (Dawson
Trick Litskow [DTL] fiber) will be placed on each eye under dim red light, and a rod response
and a maximal response (mixed) ERG will be recorded.  Following a single-flash cone
response and 31 Hz flicker response at the end of a 10-minute period of light adaptation,
subjects will undergo photobleaching for a period of 3 minutes.  Rod responses will be
recorded immediately after photobleaching and at 10, 20, and 30 minutes following the
photobleaching.
13.17 Reduced-illuminance Fundus Autofluorescence
Reduced-illuminance FAF images will be obtained to assess lesion characteristics of each eye
for all subjects. For reduced-illuminance FAF, Spectralis models must be used as described in


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the central image reading center manual. Images will be sent to the central image reading
center to confirm eligibility.
The study personnel who perform reduced-illuminance FAF will be trained and certified by the
central image reading center prior to enrollment of subjects.
13.18 Evaluation of Adverse Events
All AEs (serious and nonserious) must be recorded in the source documents and AE eCRFs,
regardless of causal relationship with study drug or procedures. AEs must be captured from
the time the subject signs the ICF through the earlier of either the final study visit or 30 days
after the last study drug dose.  The following information will be collected about each AE:
severity, onset and resolution dates and times, frequency, seriousness, relationship to study
drug, action taken, outcome, location, and whether the AE caused the subject to discontinue
from the study.
Definitions
An AE is any untoward medical occurrence in a subject administered a study drug and does not
necessarily have to have a causal relationship with the study drug.
AEs may include:

Any unfavorable sign, medical diagnosis, or symptom. Whenever possible, the
Investigator should group signs or symptoms that constitute a single diagnosis under a
single AE term (eg, “cough, rhinitis, and sneezing” might be grouped together as
“upper respiratory tract infection”).

An unfavorable change of a pre-existing condition that occurs during the
protocol-defined reporting period.

Clinically significant laboratory abnormalities, ophthalmic assessments, or vital signs.
If possible, abnormal laboratory results or changes in vital signs that meet the definition
of an AE should be reported as a clinical diagnosis, rather than the abnormal laboratory
value (eg, “hypertension” rather than “blood pressure increased”).
Special considerations include:

A medical or surgical procedure, itself, should not be captured as an AE.  The
Investigator should determine whether or not the medical condition or diagnosis
necessitating such treatment is an AE, eg, the worsening of a pre-existing condition or a
new diagnosis.


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Changes in pre-existing medical conditions, including worsening severity, frequency,
or character during the protocol-defined reporting period, should be recorded as AEs.

Death itself is not considered an AE.  The cause of death should be reported as a
serious adverse event (SAE).

Pregnancy is not an AE. Pregnancy in a female subject or the partner of a male subject
should be reported to the Sponsor in accordance with Section 13.18.4.
A treatment-emergent AE is any AE that occurs after the subject has received the first dose
of study drug, whether or not it is considered causally related to the study drug.
A serious AE includes any event that, in the view of either the Investigator or Sponsor, results
in any of the following outcomes:

Death

Life-threatening (ie, the subject was at immediate risk of death at the time of the event).
It does not refer to an event that hypothetically might have caused death if it were more
severe.

Requires inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions

A congenital anomaly/birth defect of offspring

An important medical event that might not be immediately life-threatening or result in
death or hospitalization, but might jeopardize the subject or might require intervention
to prevent one of the outcomes listed in the definition above. Examples of such events
are intensive treatment in an emergency room or at home for allergic bronchospasm,
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
AE Severity:
AEs will be graded using National Cancer Institute Common Terminology Criteria for Adverse
Events (CTCAE) v 4.03.  The criteria can be accessed at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
The term “severe” is a measure of intensity.  A severe AE is not necessarily a serious AE.


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Study Drug Causality:
Relationship of an AE to treatment will be assessed by the investigator as follows:
Causality
Definition
Related
There is a reasonable causal association with administration of
the drug; the event is confirmed by stopping and/or restarting
the drug or is not explained by any other reasonable hypothesis;
there is evidence to suggest a causal relationship between the
drug and the AE.
Not related
There is no causal or temporal relationship to the study drug
administration; the event is related to other etiologies such as
concomitant medications or conditions.
Adverse Event Reporting Procedures
Subjects will be instructed to report all AEs that occur during their study participation. The
Investigator will assess subjects for the occurrence of AEs at all scheduled and unscheduled
visits.  The occurrence of AEs should be elicited by non-direct questioning of the subject at
each visit, eg, “Have you had any problems since your last visit?” The Investigator may detect
AEs while performing a physical examination or other assessments.  All AEs (serious and
nonserious) reported by the subject will be reviewed by a qualified Investigator in the study
and must be recorded on the source documents and AE eCRFs.
An AE that is serious must be reported on an SAE form to the Sponsor’s Drug Safety
department no later than 24 hours after the Investigator becomes aware of the event.
SAE Notification
All SAEs occurring after the ICF is signed but before administration of study drug that are
considered related to a protocol procedure must also be reported to Drug Safety within 24
hours after the clinical site becomes aware of the event.


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For SAEs that occur before the first dose of study drug is administered and that are considered
unrelated to any study procedure by the Investigator, record the SAE on the AE eCRF only;
completion of an SAE form and reporting to Drug Safety is not required for such events.
If an ongoing SAE changes in intensity, outcome, or the relationship to study drug, a follow-up
SAE report should be sent to the Sponsor within 24 hours after the clinical site becomes aware
of the change in status.
Reporting Serious Adverse Events to Regulatory Agencies
The Sponsor will determine which SAEs qualify for expedited reporting.  Reports of those
SAEs that qualify for expedited reporting will be submitted to regulatory agencies in
accordance with applicable local regulation (eg, 21 Code of Federal Regulations [CFR]
312.32). Expedited reports will be also distributed to Investigators, but without revealing the
treatment assignment, and will be submitted to the IRB in accordance with institutional
guidelines and local regulation.
Pregnancy
Pregnancy itself is not an AE.  However, any report of pregnancy that occurs in a female
subject or the partner of a male subject during study participation or within 30 days after the
subject’s last dose of study drug, and that becomes known to the Investigator, must be reported
to the Sponsor even if the subject is withdrawn from study.
If a subject or Investigator suspects that a subject may be pregnant prior to study drug
administration, the study drug administration must be withheld until the results of blood serum
or urine pregnancy tests are available.  If pregnancy is confirmed, the subject must not receive
the study drug and must not be enrolled in the study.  If pregnancy is suspected while the
subject is receiving study treatment, the study drug must be withheld immediately until the
result of the serum pregnancy test is known.  If pregnancy is confirmed, the study drug will be
permanently discontinued and the subject will be withdrawn from the trial.
The Investigator must follow the pregnancy to conclusion and will collect data on both
maternal and fetal outcome including follow-up information regarding the course of the
pregnancy, including perinatal and neonatal outcome.  Normal outcomes will be communicated
to the Sponsor within 30 calendar days of birth/delivery.  Infants will be followed for a
minimum of 6 months.
Pregnancy itself should be entered as an AE in the eCRF and reported to Drug Safety on the
Pregnancy Report Form.   Any abnormal pregnancy outcome should be reported to the Sponsor


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in accordance with Section 13.18.2.  This includes spontaneous abortion and any neonatal
outcome that meets the seriousness criteria.
Overdose
Overdose is defined as any dose higher than the defined or prescribed dose of study drug.
Occurrences of overdose will be documented as protocol deviations.  An overdose resulting in
an AE will be reported on the AE eCRF.
An overdose leading to an SAE will be reported to the Sponsor in accordance with the
procedure described in Section 13.18.2.
Follow-up of Adverse Events
Subjects with ongoing SAEs will be followed until the event(s) is resolved, stabilized, no
longer considered clinically significant by the Investigator, or the subject dies or withdraws
consent.
Resolution means the subject has returned to the baseline state of health.  Stabilization means
the Investigator does not expect any further improvement or worsening in the subject’s
condition.
All nonserious AEs will be followed through the last scheduled or unscheduled visit.
For a nonserious AE that is first identified on the last scheduled contact (and with onset
≤30 days after the last study drug dose), the event must be recorded on the AE eCRF with the
current status noted, but no further follow-up needs to be performed.
Nonserious AEs which occur > 30 days after the last study drug dose will not be recorded on
the AE eCRF.
Follow-up of Post-study Serious Adverse Events
Any new SAE reported by the subject to the Investigator, with onset after the earlier of the
final study visit or 30 days after the last study drug dose and that is determined by the
Investigator to be associated with the use of study drug, should be reported to the Sponsor.
The Investigator should follow these related SAEs and continue to report any significant
follow-up information to the Sponsor until the events are resolved or stabilized, or the subject
is lost to follow-up.


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14 Data Monitoring Committee
This study will not use a Data Monitoring Committee to evaluate safety data. A Safety Review
Team consisting of Sponsor staff and/or consultants will periodically review aggregate safety
data.
15 Study Endpoints
15.1
Pharmacodynamic Endpoint
The PD endpoint is the percent suppression at the end of the 1-month treatment period
compared to baseline of the rod b-wave amplitude recovery after a photobleaching light.
15.2
Safety Endpoints
Safety endpoints will include:
1. Incidence, severity, and seriousness of AEs, and discontinuations due to AEs.
2. Change from baseline in laboratory values, vital signs, physical examination findings,
ECGs, and ophthalmic assessments.
16 Statistical Analysis and Study Variables
16.1
Determination of Sample Size
This study will enroll approximately 30 subjects with a goal of having 24 subjects (8 per
treatment arm) complete the masked treatment phase of the study.  This sample size is not
based on statistical rationale but is considered adequate to determine the PD response of each
dose of emixustat in this study population.
16.2
Data Sets to be Analyzed
The ERG variables will be analyzed using the PD set of subjects, and all safety variables will
be analyzed using the Safety Analysis (SA) set of subjects. The determination of subjects
included in these data sets will be made prior to locking the final database. These data sets are
defined below.
Pharmacodynamic Set
The PD set of subjects will include all randomized subjects who have at least 1 post-baseline
ERG performed while on study drug that is considered at least partially analyzable by the
central ERG reading center.


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Safety Analysis Set
The SA set of subjects will include all randomized subjects who took at least 1 dose of study
drug.  Subjects will be analyzed in the group according to the treatment they received, and no
subjects (or data) will be excluded from this data set because of protocol deviations that occur
during the study.
16.3
Subject Disposition
Subject disposition including the number of subjects randomized, treated with masked study
drug, completing each study visit, and completing the study will be tabulated by treatment arm.
The percentage of subjects treated and completing the study will be based on the total number
randomized.  Major protocol deviations will also be summarized by treatment arm.  Subject
discontinuations and the reasons for discontinuation will also be summarized for all
randomized subjects.
16.4
Analysis of Demographic and Baseline Data
Subject demographic and baseline data will be summarized by treatment arm for all
randomized subjects.  Continuous variables will be summarized using descriptive statistics
(number of subjects, mean, standard deviation, median, minimum, and maximum), and
categorical variables will be summarized using the count and percentage of subjects in each
category.
16.5
Compliance and Exposure
Study drug will be administered orally QD in the evening for 1 month, until the evening before
the Month 1 visit.
Subjects will be instructed to return all used and/or unused blister packs of study drug to the
clinic at the Month 1 visit for assessment of dosing compliance. Subjects will be queried
regarding compliance with the dosing regimen, and any missed doses will be documented.
Compliance and total exposure information will be summarized.
16.6
Pharmacodynamic Analysis
The primary analysis of the ERG data will be performed on the data through Month 1, and will
be performed after all subjects have either completed Study Exit visit or discontinued early
from the study, and the study database has been cleaned, verified, and locked.  It is planned
that the data from all clinical sites that participate in this study will be combined, so that the
target sample size will be available for analysis.  Further details of the statistical methods will
be included in the Statistical Analysis Plan.


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Pharmacodynamic variables will include ERG rod b-wave amplitudes and the degree of
suppression of the rod b-wave amplitude recovery following a photobleaching light.  The
degree of suppression will be determined as the percent decrease from baseline to post-
treatment in the rate of recovery of the rod b-wave amplitude during the 30-minute post-
bleaching period.  Results will be summarized by treatment group.
16.7
Safety Analysis
All safety variables will be analyzed using the SA set of subjects.  The assessment of safety
will be based on the summaries of ocular and non-ocular AEs, ophthalmic examination
findings, vital signs, physical examination findings, ECGs, and clinical laboratory values.
Subjects will be summarized in the group according to the treatment received.
Adverse events reported during the study will have their verbatim terms mapped to the
corresponding thesaurus terms from the most current version of the Medical Dictionary for
Regulatory Activities (MedDRA®) coding dictionary.  All summaries of AEs will be based on
the assigned MedDRA Preferred Term and System Organ Class, and summaries will be given
for each of the randomized treatment arms.
Separate summaries of AEs related to treatment (as reported by the Investigator) and by
severity will be prepared.  The number of SAEs will also be presented, and events leading to
discontinuation from the study will be listed and tabulated.
Other safety assessments will be presented descriptively (absolute values and changes from
baseline).  These will include total BCVA letter score, IOP, vital signs, clinical laboratory
values, and ECG findings.  Continuous variables will be summarized using descriptive
statistics, and categorical variables will be summarized using the count and percentage of
subjects in each category.  Shift tables will be prepared by treatment arm showing all
categorical changes from baseline to each study visit.
16.8
Subgroup Analysis
Because of the small number of subjects in this study, no subgroup analyses are planned.
16.9
Interim Analyses
No interim analyses are planned during this study.


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17 Data Handling and Quality Assurance
17.1
Case Report Forms
As part of the responsibilities assumed by participating in the study, the Investigator agrees to
maintain adequate case histories for the subjects treated as part of the research under this
protocol.  The Investigator agrees to maintain an accurate eCRF and source documentation as
part of the case history for each subject.  Source documentation may include chart notes,
laboratory reports, and ECG strips.
All requested information is to be filled in on the eCRF.  If an item is not available or is not
applicable, this should be indicated.  Blank data fields should not be present unless otherwise
directed.
Each completed eCRF must be reviewed, signed, and dated by the Investigator in a timely
manner.
17.2
Monitoring of the Study
The CRA, a representative of the Sponsor, will follow the study closely.  The CRA will
maintain necessary email, telephone, fax, and/or mail contact with the Investigators and study
site and will visit the study sites at periodic intervals.  The CRA will maintain current personal
knowledge of the study through observation, review of study records and source
documentation, and discussion of the conduct of the study with the Investigators and study site
staff.  During those visits, the CRA will compare the subject data recorded in the eCRF against
source documents at the clinical site. The CRA will be masked to the identity of each subject’s
treatment assignment.
All aspects of the study will be carefully monitored by the Sponsor or its designee for
compliance with applicable government regulation with respect to the International Council for
Harmonisation (ICH) guideline E6 (R1):  Good Clinical Practice (GCP):  Consolidated
Guideline and current standard operating procedures.
17.3
Inspection of Records
Investigators and institutions involved in the study will permit study-related monitoring, audits,
IRB review, and regulatory inspection(s) by providing direct access to all study records.  The
Investigator or study site may be audited by the Sponsor or its representatives and/or regulatory
agencies at any time.  In the event of an audit, the Investigator agrees to allow the Sponsor,
representatives of the Sponsor, the Food and Drug Administration (FDA), or other regulatory
agency access to all study records.


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The Sponsor will review eCRF data and perform electronic edit checks on the data.
The Investigator should promptly notify the Sponsor of any audits scheduled by any regulatory
authorities and promptly forward copies of any audit reports received to the Sponsor.
17.4
Study Record Retention
Government agency regulations and directives require that all study documentation pertaining
to the conduct of a clinical study must be retained by the investigator.  Original source
documents for each subject should be included in this documentation.  Study documentation
should be retained by the Investigator until notified by the Sponsor in writing that retention is
no longer necessary.  Study documentation includes records of laboratory tests, clinical notes,
and subject medical records.  It is the responsibility of the Sponsor to inform the
Investigator/institution as to when this documentation no longer needs to be retained.
Records containing subject medical information must be handled in accordance with the
requirements of the applicable privacy rules and consistent with the terms of the subject
authorization contained in the ICF for the study.  Care should be taken to ensure that such
records are not shared with any person or for any purpose not contemplated by the ICF.
Furthermore, eCRFs and other documents to be transferred to the Sponsor should be completed
in strict accordance with the instructions provided by the Sponsor, including the instructions
regarding the coding of subject identities.  Should the Investigator wish to assign the study
records to another party or move them to another location, written agreement must be obtained
from the Sponsor.  If requested, the Investigator will provide the Sponsor, applicable
regulatory agencies, and applicable IRB with direct access to original source documents.
Essential documents should be retained until at least 15 years after the last approval of a
marketing application in an ICH region and until there are no pending or contemplated
marketing applications in an ICH region or at least 15 years have elapsed since the formal
discontinuation of clinical development of the study drug.  These documents should be retained
for longer, however, if required by the applicable regulatory requirements or by an agreement
with the Sponsor.
18 Study Ethical Considerations
18.1
Ethical Conduct of the Study
The Investigator agrees that the study will be conducted according to the GCP principles of the
ICH E6 (R1) guideline and the principles of the World Medical Association Declaration of
Helsinki on Ethical Principles for Medical Research Involving Human Subjects 1964,


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including all amendments and Notes of Clarification.  The Investigator will conduct all aspects
of this study in accordance with all national, state, and local laws or regulations.
18.2
Informed Consent
Written informed consent in compliance with Title 21 of the CFR Part 50 shall be obtained
from each subject prior to entering the study or performing any unusual or non-routine
procedure that involves risk to the subject.  An ICF template may be provided by the Sponsor
or designee to investigative sites.  The ICF will be submitted by the Investigator to his or her
IRB for review and approval prior to the start of the study.  If any institution-specific
modifications to study-related procedures are proposed or made by the site, the ICF should be
reviewed by the Sponsor and/or its designee, if appropriate, prior to IRB submission.  If the
ICF is revised during the course of the study, all active participating subjects must sign the
revised form.
Before recruitment and enrollment, each prospective subject will be given a full explanation of
the nature of the study and the action of the study drug.  The subject will be informed that
participation is voluntary and that they can withdraw from the study at any time.  The subject
will be allowed to read the approved ICF.  Once the Investigator is assured that the subject
agrees to participate in the study, the subject will be asked to give consent by signing the ICF.
The Investigator shall provide a copy of the signed and dated ICF to the subject.  The original
shall be maintained in the subject’s medical records at the site. The informed consent process
will be documented in the subject’s medical records.
18.3
Institutional Review Board
Federal regulations and ICH guidelines require that approval be obtained from an IRB prior to
participation of human subjects in research studies.  Prior to the study onset at any given
Investigator site, an appropriate IRB must approve the protocol, ICF, advertisements to be used
for subject recruitment, and any other written information regarding this study that is to be
provided to the subject.  Documentation of all IRB approvals and of the IRB compliance with
the ICH E6 (R1) guideline will be maintained by the site and will be available for review by
the Sponsor or its designee.
All IRB approvals should be signed by the IRB chairperson or designee and must identify the
IRB by name and address, the clinical protocol by title and/or protocol number and version or
date, and the date approval and/or favorable opinion was granted.
The Investigator will supply the following to the investigative site’s IRB:

Protocol and amendments


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Informed consent form and updates

Investigator’s Brochure and updates

Relevant curricula vitae, if required

Required safety and SAE reports

Any additional submissions required by the site’s IRB
The Investigator must provide written documentation of the following to the Sponsor or
designee:

IRB periodic (eg, quarterly, annual) re-approval of the protocol, as required by the IRB

IRB approvals of any amendments to the protocol or revisions to the ICF

IRB receipt of safety and SAE reports, as appropriate
19 Administrative Considerations
19.1
Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified in a
manner designed to maintain subject confidentiality.  All records will be kept in a secure
storage area with limited access.  Clinical information will not be released without the written
permission of the subject, except as necessary for monitoring and auditing by the Sponsor, its
designee, the FDA (or other international regulatory agency), or the IRB.
The Investigator and all employees and coworkers involved with this study may not disclose or
use for any purpose other than performance of the study, any data, record, or other unpublished
confidential information disclosed to those individuals for the purpose of the study.  Prior
written agreement from the Sponsor or its designee must be obtained for the disclosure of any
said confidential information to other parties.
19.2
Modification of the Protocol
The Investigator may implement a change from the protocol without prior Sponsor and IRB
approval only to eliminate an immediate hazard to a subject, in which case, Sponsor and IRB
must be notified of the change within 24 hours.
Amendments to the protocol must be submitted in writing to the FDA and/or other regulatory
agencies and IRB and approved prior to subjects being enrolled into an amended protocol.


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19.3
Protocol Deviations
A protocol deviation occurs when the Investigator or subject has failed to adhere to protocol
requirements.  All significant deviations related to study inclusion or exclusion criteria,
conduct of the trial, subject management or subject assessment should be documented.
Specific categories to be documented include but are not limited to:

Subjects who enter the study even though they do not satisfy the entry criteria

Subjects who develop withdrawal criteria during the study but are not withdrawn

Subjects who receive the wrong treatment or incorrect dose

Subjects who receive a prohibited concomitant treatment
Other protocol deviations to be considered include nonadherence to the protocol that results in
a significant additional risk to the subject.
The Investigator must document and explain any protocol deviation in the subject’s source
documentation.  The IRB should be notified of important protocol deviations in a timely
manner, in accordance with IRB requirements.  Protocol deviations should be reported to the
IRB periodically, according to their requirements.  Protocol deviations will also be documented
by the clinical monitor during monitoring visits and those observations will be reviewed with
the Investigator.
The Investigator is responsible for enrolling subjects who have met protocol eligibility criteria.
If the Investigator has a question concerning a subject who may not meet an entry criterion,
they should contact the Medical Monitor to discuss the specifics. Waivers for protocol
eligibility will not be granted in this study.
19.4
Study Reporting Requirements
By participating in this study, the Investigator agrees to submit reports of SAEs according to
the timeline and method outlined in the protocol.  In addition, the Investigator agrees to submit
periodic reports to his/her IRB as appropriate.
19.5
Financial Disclosure
Principal Investigators and Sub-investigators are required to provide financial disclosure
information to allow the Sponsor to submit the complete and accurate certification or
disclosure statements required under Title 21 CFR 54.  In addition, the Investigator must
provide to the Sponsor a commitment to update this information promptly, if any relevant
changes occur during the course of the investigation, at the completion of the trial, and 1 year
following the completion of the study.


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19.6
Financial Obligations
The Sponsor is not financially responsible for further testing/treatment of any medical
condition that may be detected during the screening process.  In addition, in the absence of
specific arrangements, the Sponsor is not financially responsible for further treatment of the
subject’s disease.
19.7
Investigator Documentation
Prior to beginning the study, the Investigator will be asked to comply with ICH E6 (R1),
Section 8.2 and Title 21 CFR by providing the following essential documents, including but
not limited to:

An Investigator-signed Investigator Agreement page of the protocol (Section 20)

An IRB-approved ICF, samples of site advertisements for recruitment for this study, and
any other written information regarding this study that is to be provided to the subject

IRB approval of the Investigator and protocol

IRB acknowledgement of receipt of the Investigator’s Brochure

Form FDA 1572, fully executed, and all updates on a new fully executed
Form FDA 1572

Curricula vitae for the Principal Investigator and each Sub-investigator listed on
Form FDA 1572.  Current licensure must be noted on the curricula vitae or a copy of the
license provided.  The curricula vitae must be signed and dated by the Principal
Investigators and Sub-investigators within 1 year of study start-up, indicating that they
are accurate and current.

Financial disclosure information to allow the Sponsor to submit complete and accurate
certification or disclosure statements required under Title 21 CFR 54.  In addition, the
Investigators must provide to the Sponsor a commitment to promptly update this
information if any relevant changes occur during the course of the investigation, at the
completion of the trial, and 1 year following the completion of the study.
19.8
Clinical Trial Agreement
Payments by the Sponsor to Investigators and institutions conducting the study, requirements
for Investigators’ insurance, and other requirements are specified in the Clinical Trial
Agreement.


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19.9
Policy for Publication and Presentation of Data
Following completion of the study at all sites, data may be considered for reporting at a
scientific meeting and/or for publication in a scientific journal.  Draft manuscripts of any
public disclosure shall be provided to the Sponsor 60 days prior to presentation or publication
in order to enable the Sponsor to review and comment and take any steps necessary to protect
its intellectual property rights, consistent with the Clinical Trial Agreement.


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20 Investigator Agreement
I agree to conduct the study as outlined in the protocol entitled, “A Phase 2a Multicenter,
Randomized, Masked Study Evaluating the Pharmacodynamics of Emixustat Hydrochloride in
Subjects with Macular Atrophy Secondary to Stargardt Disease,” and in accordance with
generally accepted standards of GCP, and all applicable guidelines and government regulations
including Title 21 CFR 54.  I agree to provide the Sponsor with accurate financial information
to allow the Sponsor to submit complete and accurate certification and disclosure statements as
required by applicable regulations.
I have read and understand all sections of the protocol, including the sections on study ethical
considerations (Section 18) and administrative considerations (Section 19).
Principal Investigator’s Name
Principal Investigator’s Signature
Date


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21 References
1. Blacharski PA. Fundus flavimaculatus. In: Newsome, DA, ed. Retinal dystrophies and
degenerations. New York: Raven Press, 1988:135-159.
2. Abdollahi S, Hirose T. Stargardt-fundus flavimaculatus: Recent Advancements and
Treatment. Seminars in Ophthalmology, 2013; 28(5–6):372–376.
3. Molday RS. Insights into the molecular properties of ABCA4 and its role in the visual
cycle and Stargardt disease. Prog Mol Biol Transl Sci. 2015;134:415-31.
4. Chen Y, Okano K, Maeda T, et al. Mechanism of all-trans-retinal toxicity with
implications for Stargardt disease and age-related macular degeneration. J Biol Chem.
2012 Feb 10; 287(7):5059-69.
6. Bavik C, Henry SH, Zhang Y, Mitts K, McGinn T, Budzynski E, et al. Visual Cycle
Modulation as an Approach toward Preservation of Retinal Integrity. PLoS ONE.
2015;10(5):e0124940.
7. Kubota R, Al-fayoumi S, Mallikaarjun S, Patil S, Bavik C, Chandler JW. Phase 1, dose-
ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator,
in healthy volunteers. Retina. 2014;34(3):603-9.


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22 Appendices


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22.1 Appendix A:  Summary of Changes for Amendments
Protocol Amendment 1, Summary of Changes, dated 13 July 2017
Section
Changed
Initial Protocol
(Changed From)
Modified Protocol
(Changed To)
Reason for Change
Impact on
Subjects
(Risk/Benefit)
Title page
Acucela Inc
1301 Second Ave, Suite 4200
Seattle, WA 98101-3805
Acucela Inc
818 Stewart St, Suite 1110
Seattle, WA 98101
Sponsor address
change
None
Section 2, Key
Roles and
Contacts
Acucela Inc
1301 Second Ave, Suite 4200
Seattle, WA 98101-3805
Acucela Inc
818 Stewart St, Suite 1110
Seattle, WA 98101
Sponsor address
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Section 9.2,
Inclusion
Criteria
4. Total area of definitely decreased
autofluorescence MA in the study eye equal
to 1.25 - 18 mm2 (~0.5 – 7 disc areas) in
size as determined by the central image
reading center’s assessment of fundus
autofluorescence (FAF) imaging at
Screening.
4. Total area of MA (definitely decreased
autofluorescence plus questionably decreased
autofluorescence)  in the study eye equal to 1.25 -
26 mm2 (~0.5 – 10.25 disc areas) in size as
determined by the central image reading center’s
assessment of fundus autofluorescence (FAF)
imaging at Screening.
Allows a broader
population to be
enrolled.
None