Conditions: Proliferative Diabetic Retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
To evaluate the effects of oral emixustat hydrochloride (emixustat) on aqueous humor biomarkers associated with proliferative diabetic retinopathy (PDR) from baseline to week 12.

Detailed description:
This is a multicenter, randomized, double-masked, placebo-controlled study to evaluate the effects of emixustat in subjects with PDR. Subjects will be randomly assigned to either emixustat or placebo arms and treated once daily (QD) for 12 weeks. Doses of emixustat will be doubled on a weekly basis until week 4 after which all subjects will be held at a stable dose for the remainder of the 12-week dosing regimen. Subjects in the placebo group will be mock-titrated on the same schedule as those in the emixustat arm.

Arms:
arm 1: Week 1- Four tablets (2 placebo, 2 emixustat HCl Strength A)

Week 2- Four tablets (2 placebo, 2 emixustat HCl Strength B)

Week 3- Four tablets (2 placebo, 2 emixustat HCl Strength C)

Week 4- Four emixustat HCl tablets (Strength C)

All tablets are administered orally once daily. After week 4, all subjects will be held at a stable dose for the remainder of the 12-week dosing regimen. arm 2: Four placebo tablets are administered orally once daily for 12 weeks; Subjects in the placebo group will be mock-titrated on the same schedule as those in the active arm.

Interventions: intervention 1: emixustat hydrochloride intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet for oral administration intervention 2: Placebo tablets for oral administration contain only inactive ingredients

Protocol document:
Prot_SAP_000.pdf: 
Acucela Inc 
Protocol 
Emixustat Hydrochloride 
Study 4429-203, Original 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Masked, 
Placebo-Controlled, Pilot Study to Evaluate Effects of 
Emixustat Hydrochloride on Aqueous Humor 
Biomarkers Associated with Proliferative Diabetic 
Retinopathy 
PROTOCOL NUMBER: 
4429-203 
NAME OF TEST ARTICLE: 
Emixustat hydrochloride 
INDICATION: 
Proliferative Diabetic Retinopathy 
DEVELOPMENT PHASE: 
Phase 2 
STUDY DESIGN: 
Multicenter, randomized, double-masked, placebo-
controlled, parallel-group  
SPONSOR: 
Acucela Inc. 
1301 Second Ave, Suite 4200 
Seattle, WA 98101-3805 
DATE OF PROTOCOL: 
05 February 2016 
The information contained in this document, particularly unpublished data, is the property or under control of 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 Conference 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: 
 
         02753400




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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. 
1301 Second Ave, Suite 4200 
Seattle, WA 98101-3805 
Phone: 206-805-8300 
  
 
 
 
  
 
        
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
Protocol Summary 
Protocol Number: 
4429-203 
Protocol Title: 
A Multicenter, Randomized, Double-Masked, Placebo-Controlled, 
Pilot Study to Evaluate Effects of Emixustat Hydrochloride on 
Aqueous Humor Biomarkers Associated with Proliferative Diabetic 
Retinopathy 
Phase: 
Phase 2 
Study Objectives 
Primary: 
To evaluate the effects of oral emixustat hydrochloride (emixustat) on 
aqueous humor biomarkers (interleukin [IL]-6, IL-8, interferon-
gamma inducible protein [IP]-10, platelet-derived growth factor 
[PDGF]-AA, transforming growth factor [TGF]β-1, monocyte 
chemo-attractant protein [MCP]-1, IL-1β, and vascular endothelial 
growth factor [VEGF]) associated with proliferative diabetic 
retinopathy (PDR) from baseline to Day 85 
Secondary: 
To evaluate the effects of oral emixustat on: 
1. Change in area of retinal neovascularization (NV) from 
baseline to Day 85 
2. Change in degree of vitreous hemorrhage from baseline to 
Day 85 
3. Change in degree of preretinal hemorrhage from baseline to 
Day 85 
4. Change in normal luminance best-corrected visual acuity (NL-
BCVA) from baseline to Day 85 
5. Change in central subfield thickness (CST) as assessed from 
spectral domain optical coherence tomography (SD-OCT) 
from baseline to Day 85 in subjects with diabetic macular 
edema (DME) 
6. Change in retinal vessel oxygen saturation as measured by 
retinal oximetry imaging from baseline to Day 85 
7. Safety and tolerability compared to placebo when 
administered orally for 84 days 


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Exploratory: 
n/a 
Study Population: 
Subjects newly or recently diagnosed with PDR, with or without 
DME 
Study Design: 
This is a multicenter, randomized, double-masked, placebo-controlled 
study to evaluate the effects of emixustat in subjects with PDR. 
Subjects will be randomly assigned to one the following treatment 
arms in a 1:1 ratio: 
• Emixustat, up to 40 mg (step-up titration) 
• Placebo 
Subjects will be treated once daily (QD), in the evening, for a total of 
84 days. Subjects assigned to the emixustat arm will receive 5 mg QD 
oral emixustat for the first week, then the dose will be doubled on a 
weekly basis to 10 mg QD (week 2), 20 mg QD (week 3), and 40 mg 
QD (week 4). Subjects who do not tolerate dose escalations will be 
returned to and held stable at the last tolerated dose; after week 4, all 
subjects will be held at a stable dose for the remainder of the study. 
Dose reduction may be undertaken only once and is only available at 
Visit 4, Visit 5, or Visit 6. 
Subjects in the placebo group will be mock-titrated on the same 
schedule as those in the step-up titration arm.  
Number of Subjects: 
Approximately 20 subjects from up to 7 clinical sites in the United 
States will be enrolled. 
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. Able and willing to provide a written informed consent before 
undergoing any study-related procedures. 
2. In the opinion of the investigator, the ability and willingness 
to return for all scheduled visits and perform all assessments.  
3. Males or females, ≥ 18 and ≤ 85 years of age at the Screening 
Visit.  


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4. A documented diagnosis of type 1 or type 2 diabetes mellitus. 
Any one of the following will be sufficient evidence that 
diabetes is present: 
a. Current regular use of insulin for the treatment of 
diabetes 
b. Current regular use of an oral anti-hyperglycemia 
agent for the treatment of diabetes 
c. Documented diabetes by American Diabetes 
Association (ADA) and/or World Health Organization 
(WHO) criteria (see Appendix C for definitions) 
5. The following ocular criteria for the study eye: 
a. Presence of PDR with or without DME for which, in 
the Investigator's judgment, interventional treatment 
can be safely deferred for at least 4 weeks after the 
Day 1 visit. 
b. No prior pan-retinal photocoagulation (PRP); defined 
as ≥ 500 burns placed previously outside the posterior 
pole. 
c. No intravitreal injection of an anti-VEGF agent in the 
3 months prior to randomization (Day 1). 
d. No intravitreal or peri-bulbar injection of a 
corticosteroid in the 4 months prior to randomization 
(Day 1). 
e. Early Treatment Diabetic Retinopathy Study (ETDRS) 
NL-BCVA letter score of ≥ 24 (approximate Snellen 
equivalent 20/320) on the day of randomization (Day 
1). 
f. Media clarity, pupillary dilation, and subject 
cooperation sufficient to obtain adequate fundus 
photographs and SD-OCT. 


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Exclusion Criteria: 
Subjects will be excluded from participation in the study if they meet 
any of the following criteria at screening and baseline (unless 
otherwise indicated): 
1. Any condition that, in the opinion of the investigator, would 
preclude participation in the study (eg, unstable medical status 
including blood pressure, cardiovascular disease, or glycemic 
control). 
2. Subjects with poor glycemic control, including those who 
initiated intensive insulin treatment (a pump or multiple daily 
injections) in the 4 months prior to Screening, or plan to do so 
in the next 4 months. 
3. Significant renal disease, defined as a history of chronic renal 
failure requiring dialysis or kidney transplant. 
4. Elevated blood pressure (defined as > 180/110; systolic above 
180 or diastolic above 110). Subjects with elevated blood 
pressure, when attributable to specific circumstances (eg, 
missed medication, stress etc.), may be retested on the same or 
later date, as appropriate (within the period between Screening 
and randomization (Day 1). 
5. History of myocardial infarction or other acute cardiac event 
requiring hospitalization, stroke, transient ischemic attack, or 
treatment for acute congestive heart failure within 60 days 
prior to randomization. 
6. Previous participation (ie, randomization) in a study of 
emixustat. 
7. Participation (ie, randomization) in another investigational 
trial within 30 days of the Screening Visit that involved 
treatment with any drug that has not received regulatory 
approval for the indication being studied.  
8. Known allergies to fluorescein sodium for injection in 
angiography, to emixustat, or to any excipients in the 
emixustat tablets (ie, silicified microcrystalline cellulose, pre-
gelatinized starch, colloidal silicon dioxide, or stearic acid).  


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9. Prohibited medications:  
a. Systemic use of a strong inducer of or a strong or 
moderate inhibitor of cytochrome P450 2D6 
(CYP2D6;as listed in Appendix B) beginning 4 weeks 
prior to screening and throughout the duration of the 
study period. 
b. Anti-coagulant therapy (eg, heparins, warfarin, other 
oral anti-coagulants) beginning 14 days prior to 
screening and throughout the duration of the study.  
Anti-platelet therapy (eg, aspirin, clopidogrel) is 
allowed. 
10. History of systemic anti-VEGF or pro-VEGF treatment within 
4 months prior to randomization or plan for such treatment 
during the course of the study. 
11. Any of the following laboratory abnormalities at screening: 
a. Aspartate transaminase (AST)/alanine transaminase 
(ALT) >3.0 x upper limit of normal (ULN) 
b. Total bilirubin >1.5 x ULN 
c. Estimated glomerular filtration rate (eGFR) < 
60 mL/min/1.73 m2 
d. Impaired coagulation: International Normalized Ratio 
(INR), prothrombin time (PT), or activated partial 
thromboplastin time (aPTT) >1.25 x ULN   
e. Impaired hematologic function: 
hemoglobin <9.0 g/dL; neutrophil count <1.6 x 109/L; 
or platelet count <100 x 109/L  
f. Any laboratory screening test that meets the 
abnormality criteria stated above can be repeated once 
within the period from screening to baseline.  
12. Any of the following ocular characteristics in the study eye: 
a. Tractional retinal detachment involving the macula. A 
tractional retinal detachment is not an exclusion if it is 


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outside the posterior pole (not threatening the macula) 
and, in the Investigator’s opinion, is not considered a 
contraindication to deferring PRP, anti-VEGF therapy, 
or surgical intervention. 
b. Exam evidence of NV of the angle (NV of the iris 
alone is not an exclusion if it does not preclude 
deferring PRP or anti-VEGF therapy) 
c. A decrease in BCVA due to causes other than diabetic 
retinopathy (eg, foveal atrophy, pigment 
abnormalities, dense sub-foveal hard exudates, 
previous vitreoretinal surgery, non-retinal condition, 
substantial cataract, or macular ischemia) in the 
Investigator’s opinion. 
d. An ocular condition (other than diabetic retinopathy) 
that, in the opinion of the Investigator, might alter 
visual acuity during the course of the study (eg, retinal 
vein or artery occlusion, uveitis or other ocular 
inflammatory disease, neo-vascular glaucoma, etc.). A 
vitreous or preretinal hemorrhage is not an exclusion if 
it is out of the visual axis and, in the Investigator’s 
judgement, is not having any effect on visual acuity. 
e. History of major ocular surgery (including vitrectomy, 
cataract extraction, scleral buckle, any intraocular 
surgery, etc.) within 3 months prior to the Screening 
Visit or anticipated to occur during the course of the 
study. 
f. History of YAG posterior capsulotomy performed 
within 2 months prior to randomization (Day 1) or 
anticipated during the course of the study. 
g. Aphakia 
h. Uncontrolled glaucoma (in the Investigator’s 
judgement). 


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i. Exam evidence of periocular or ocular infection (eg, 
blepharitis, chalazion, or conjunctivitis). 
j. Implantation of any of the following intraocular 
corticosteroid implants in the timeframe indicated: 
i. Fluocinolone acetonide (Iluvien®), in the 30 
months prior to randomization (Day 1) 
ii. Dexamethasone (Ozurdex®), in the 4 months 
prior to randomization 
iii. Any other corticosteroid implant, in the 4 
months prior to randomization  
k. Macular edema due to anything other than DME (eg, 
post ocular surgery, age-related macular degeneration, 
uveitis, retinal vein occlusion, or drug toxicity) 
13. Change in a systemic prescription medication or a systemic 
medication newly prescribed within 30 days prior to screening 
and between screening and baseline or anticipated during the 
course of the study. 
14. Presence of other disease, physical examination finding, or 
clinical laboratory finding that, in the opinion of the 
Investigator, gives reasonable suspicion of a disease or 
condition which contraindicates the use of an investigational 
drug, places the subject at risk by participating in the study, or 
confounds the ability to interpret data from the study.  
15. Current or history of cancer (except for adequately treated 
basal cell or squamous cell carcinoma of the skin) within 1 
year prior to screening. 
16. Electrocardiogram (ECG) 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. 
17. Female subjects who are pregnant or lactating. 


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18. 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 following the 
completion of the study. Medically accepted methods of birth 
control include abstinence, hormonal contraceptives, non-
hormonal intrauterine contraceptive device with spermicide, 
condom with spermicide, contraceptive sponge with 
spermicide, diaphragm with spermicide, or cervical cap with 
spermicide. 
19. 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 completion 
of the study. 
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 investigator should select the study eye as the 
eye with the least potential to require PRP, anti-VEGF therapy, or 
local corticosteroids during the study, in his/her opinion.  
Test Product, Dose, 
and Mode of 
Administration: 
Emixustat (2.5, 5, or 10 mg) tablets or placebo will be packaged in 
identical, tamper-proof, blister packaging to maintain masking. 
Study drug will be taken orally, QD, in the evening for 84 days.  
During Week 1, subjects randomized to emixustat will receive 4 
tablets (two placebo, two 2.5 mg) per day for a 5 mg dose. During 
Week 2, subjects will receive 4 tablets (two placebo, two 5 mg) per 
day for a 10 mg dose. During Week 3, subjects will receive 4 tablets 
(two placebo, two 10 mg) per day for a 20 mg dose. During Weeks 4 
through 12, subjects will receive four 10 mg tablets per day for a 
40 mg dose. Subjects who do not tolerate dose escalations will be 
returned to and held at the last tolerated dose; after Week 4, all 
subjects will be held at a stable dose for the remainder of the study. 


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Dose reduction may be undertaken only once and is only available at 
Visit 4, Visit 5, or Visit 6. 
Reference Product, 
Dose, and Mode of 
Administration: 
Placebo tablets will be packaged in identical appearing, tamper-proof, 
blister packaging to maintain masking. The placebo arm will include 
identical tablets with only inactive ingredients (0 mg emixustat).  
Subjects will receive 4 placebo tablets per day. 
Study Procedures: 
The scheduled visits include Screening (within 30 days prior to 
baseline), baseline (Day 1), and days 8, 15, 22, and 29 (±1 day) and 
days 57 and 85 (±5 days). The Day 85 visit will be one day after the 
last drug/placebo treatment.  A Study Exit visit will be performed 30 
days (±5 days) after the last dose of study drug. 
Screening: The screening visit (Visit 1) will occur within 30 days 
prior to baseline. Subjects who consent to participate will have a 
screening visit at which eligibility criteria will be reviewed, 
demographic data, previous/concomitant medications and 
medical/surgical/ocular history will be collected; abbreviated physical 
exam, vital signs, and 12-lead ECG will be performed; samples will 
be obtained for safety laboratory tests (blood chemistry, hematology, 
coagulation, urinalysis), including glycosylated hemoglobin A1c 
(HbA1c) and a serum pregnancy test for women of childbearing 
potential; NL-BCVA, ophthalmic exams (slit lamp, dilated 
ophthalmoscopy, intraocular pressure [IOP], gonioscopy), and SD-
OCT will be performed.  
Masked Dose Escalation Phase: At Visit 2 (Baseline, Day 1), 
eligibility criteria will be reviewed again, and qualifying subjects will 
be randomized to 1 of the 2 treatment arms. Previous/concomitant 
medications and medical/surgical/ocular history will be reviewed, 
vital signs will be assessed, and samples for safety laboratory tests 
will be obtained (if Day 1 is >14 days after the screening visit); a 
urine pregnancy test will be performed in women of childbearing 
potential; NL-BCVA and LL-BCVA will be done, and ophthalmic 
examinations (slit lamp, dilated ophthalmoscopy, IOP, gonioscopy), 
fluorescein angiography (FA), color fundus photographs, SD-OCT, 
and retinal oximetry imaging (selected sites) will be performed.  A 50 


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μl sample of aqueous humor will be collected from the study eye by 
paracentesis and shipped the same day on dry ice.  
A one week supply of study drug (5 mg emixustat or placebo) will be 
dispensed, and subjects will self-administer drug (4 tablets) orally, 
QD, in the evening for 7 (± 1) days. Adverse events (AEs) will be 
assessed. 
At Visit 3 (Day 8 ± 1), subjects return for study drug, review of 
concomitant medications, and assessment of AEs; each subject will 
receive a 1 week supply of double the dose received at Visit 2 (10 mg 
emixustat or placebo), to be dispensed for self-administration, orally, 
QD (4 tablets) in the evening for 7 days (± 1 day).  
At Visit 4 (Day 15 ± 1), subjects return for study drug, a review of 
concomitant medications, and assessment of AEs; each subject will 
receive a 1 week supply of double the dose received at Visit 3 (20 mg 
emixustat or placebo), to be dispensed for self-administration, orally, 
QD, in the evening, for 7 days (± 1 day).  
At Visit 5 (Day 22 ± 1), subjects return for study drug, a review of 
concomitant medications, and assessment of AEs; each subject will 
receive a 1 week supply of double the dose received at Visit 4 (40 mg 
emixustat or placebo), to be dispensed for self-administration, orally, 
QD (4 tablets) in the evening for 7 days (± 1 day). 
Subjects who do not tolerate dose escalations due to AEs that, in the 
opinion of the investigator would otherwise lead to discontinuation of 
study drug will be returned to and held stable at the last tolerated dose 
(ie, dose reduction).  Dose reduction may only be undertaken once 
and is only available at Visit 4 (Day 15), Visit 5 (Day 22), or Visit 6 
(Day 29). 
Masked, Fixed Dose Phase: At Visit 6 (Day 29 ± 1), subjects return 
for study drug; a review of concomitant medications, urine pregnancy 
test (for women of childbearing potential), NL-BCVA, ophthalmic 
exams (slit lamp biomicroscopy, IOP, dilated ophthalmoscopy), SD-
OCT, and retinal oximetry imaging (selected sites) will be performed. 
Each subject will receive a 4-week supply of study drug (40 mg 
emixustat or the last tolerated emixustat dose; or placebo), to be 


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dispensed for self-administration, orally, QD (4 tablets) in the 
evening for 28 days. 
At Visit 7 (Day 57 ± 5), subjects return for study drug; a review of 
concomitant medications, urine pregnancy test (for women of 
childbearing potential), NL-BCVA, ophthalmic exams (slit lamp 
biomicroscopy, IOP, dilated ophthalmoscopy), SD-OCT, and retinal 
oximetry imaging (selected sites) will be performed. Each subject 
will receive a 4-week supply of study drug (40 mg emixustat or the 
last tolerated emixustat dose; or placebo), to be dispensed for self-
administration, orally, QD (4 tablets), in the evening for 28 days. 
One day after the last dose of study drug, subjects return on Visit 8 
(Day 85 ± 5 days) for a review of concomitant medications, and a 
urine pregnancy test (for women of childbearing potential) and vital 
signs recheck; samples for safety laboratory tests (including HbA1c) 
will be collected, and an abbreviated physical exam and 12-lead ECG 
will be performed; NL-BCVA and LL-BCVA will be measured, and 
ophthalmic examinations (slit lamp biomicroscopy, IOP, dilated 
ophthalmoscopy, gonioscopy), FA, color fundus photography, SD-
OCT, and retinal oximetry imaging (selected sites) will be conducted. 
A 50 μl sample of aqueous humor will be collected from the study 
eye by paracentesis and shipped the same day on dry ice. 
Study Exit: A Study Exit visit will be performed 30 days (± 5 days) 
after the last dose of study drug. Concomitant medications will be 
reviewed and a urine pregnancy test (for women of childbearing 
potential), NL-BCVA, SD-OCT, and ophthalmic examinations (slit 
lamp biomicroscopy, IOP, dilated ophthalmoscopy) will be 
performed. 
Rescue Treatment Criteria for PDR: All subjects will be eligible 
for PRP or anti-VEGF therapy for PDR in the study eye as of Day 29 
(Visit 6) of the study if the following criterion is met: 
• There is new NV or growth of NV of the retina, disc, angle, 
OR iris such that the NV is greater in extent than at Day 1 
(Visit 2/Baseline). 
Rescue Treatment Criteria for DME: 


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All subjects will be eligible for therapy for DME in the study eye as 
of Day 29 (Visit 6) of the study if either of the following criteria are 
met: 
a. Development or worsening of DME as illustrated by an 
increase in central retinal thickness of ≥100 microns from any 
previous visit (as measured by the Investigator). 
b. A BCVA decrease of ≥10 letters from any previous visit that 
is deemed secondary to DME. 
Subjects for whom it is determined that treatment with PRP, anti-
VEGF therapy, or local corticosteroids in the study eye is necessary 
will discontinue study drug, be discontinued from the study, and 
undergo Early Termination assessments prior to any of these 
therapies. 
PRP, anti-VEGF agent therapy, focal laser therapy, or local 
corticosteroid therapy in the non-study eye is allowed at any time, at 
the Investigator’s discretion.   
Early Termination from Study:  Subjects who discontinue from the 
study early will undergo an Early Termination visit where all Day 85 
visit assessments will be performed 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.  
Subjects who have received study drug for less than 21 days will not 
undergo collection of an aqueous humor sample at the Early 
Termination visit.  If the Early Termination visit occurs ≥25 days 
after last study drug dose, the Early Termination and Study Exit visits 
may be combined.  
Criteria for Evaluation 
Variables: 
   Efficacy 
Efficacy variables will include: 
1. Aqueous humor concentration of the following biomarkers: 
IL-6, IL-8, IP-10, PDGF-AA, TGFβ-1, MCP-1, IL-1β, and 
VEGF 
2. Area of retinal NV 
3. Degree of vitreous hemorrhage 
4. Degree of preretinal hemorrhage 


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5. NL-BCVA 
6. CST as assessed by SD-OCT in subjects with DME 
7. Retinal vessel oxygen saturation  
Pharmacodynamic: 
Cytokine assessments constitute the pharmacodynamic efficacy 
variables.  
Safety: 
Safety variables will include AEs, NL-BCVA, LL-BCVA, slit-lamp 
biomicroscopy, SD-OCT, IOP, gonioscopy, dilated ophthalmoscopy, 
physical examination findings, vital signs, ECGs, and clinical 
laboratory tests. Pregnancy tests will be conducted in women of 
childbearing potential. 
Study Endpoints  
Primary Efficacy: 
The primary study endpoints are the change in aqueous humor 
concentration of eight biomarkers (IL-6, IL-8, IP-10, PDGF-AA, 
TGFβ-1, MCP-1 and IL-1β, and VEGF) from baseline (Day 1) to 
Day 85, the conclusion of a 84-day course of study drug. Analysis 
will include both absolute change and percent change from Baseline 
(Visit 2/Day 1) to Day 85 (Visit 8/Study Exit).    
Secondary Efficacy: 
The secondary efficacy endpoints will include the change in the 
following between the Baseline Visit and Day 85 (Visit 8): 
1. Area of retinal NV 
2. Degree of vitreous hemorrhage  
3. Degree of preretinal hemorrhage 
4. NL-BCVA 
5. CST as assessed by SD-OCT in subjects with DME. 
6. Retinal vessel oxygen saturation 
Statistical Analyses: 
Eight subjects per arm yields 80% power to detect a difference 
between emixustat and placebo in each aqueous humor biomarker, 
assuming an effect size of 1.31, using a two-sample t-test and a two-
sided alpha level of 0.10. To account for potential early termination 
subjects, two additional subjects per treatment arm, for a total of 10 
subjects per arm, will be enrolled.  
 
Primary and secondary endpoints will be summarized using standard 
quantitative (sample size, mean, SD, median, minimum, maximum, 
and 90% and 95% t-distribution confidence intervals [CI] around the 
mean) and qualitative (frequency counts,  percentages, and exact 90% 


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and 95% CIs around the percentages) summary statistics and assessed 
using two-sided 90% and 95% t-distribution CIs and two-sided, two-
sample t-tests around the differences between treatment groups for 
quantitative measures.  For the assessment of changes from baseline 
in aqueous humor concentration of the 8 biomarkers, both absolute 
and percent changes will be analyzed. Additionally for quantitative 
measures, 1-sample t-tests will be completed on the change from 
baseline values within a treatment group.  Qualitative measures will 
be analyzed by exact McNemar’s test for changes within a treatment 
group and Fisher’s Exact Test for differences between treatment 
groups.  Differences in proportions and 90% and 95% CIs will also be 
presented for comparisons between treatment groups for qualitative 
variables. 
Study Duration: 
The protocol calls for up to 30 days between initial screening and 
baseline (Day 1), an 84-day dosing duration and follow-up 30 days 
after last study drug dose; this yields a total duration of ~ 20 weeks, 
or 5 months.  
 
 
 


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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 .................................................................... 18 
LIST OF IN-TEXT TABLES ....................................................................... 22 
LIST OF IN-TEXT FIGURES ..................................................................... 22 
5 
Glossary of Abbreviations and Definition of Terms ........................... 23 
6 
Introduction .......................................................................................... 25 
6.1 
Background .......................................................................................................25 
6.2 
Rationale for the Study ......................................................................................25 
6.3 
Rationale for Dose Selection .............................................................................31 
7 
Study Objectives .................................................................................. 33 
7.1 
Primary Objective..............................................................................................33 
7.2 
Secondary Objectives ........................................................................................33 
7.3 
Exploratory Objectives ......................................................................................33 
8 
Investigational Plan ............................................................................. 34 
8.1 
Overall Study Design and Plan .........................................................................34 
8.2 
Number of Subjects ...........................................................................................36 
8.3 
Study Sites .........................................................................................................36 
8.4 
Discussion of Study Design, Including the Choice of Control Groups.............36 
8.5 
Efficacy Variables .............................................................................................36 
8.6 
Pharmacodynamic Variables .............................................................................36 
8.7 
Safety Variables ................................................................................................37 
9 
Study Population .................................................................................. 38 
9.1 
Target Population ..............................................................................................38 
9.2 
Inclusion Criteria ...............................................................................................38 
9.3 
Exclusion Criteria ..............................................................................................39 
9.4 
Determination of Study Eye ..............................................................................42 
9.5 
Enrollment and Subject Identification Numbers ...............................................42 


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9.6 
Subject Withdrawal from Treatment or Study ..................................................43 
9.7 
End of Study ......................................................................................................44 
10 
Randomization and Masking ............................................................... 45 
10.1 
Randomization...................................................................................................45 
10.2 
Masking .............................................................................................................45 
11 
Study Treatments ................................................................................. 47 
11.1 
Drug Dosage and Administration ......................................................................47 
11.2 
Supply, Packaging, Labeling, and Storage ........................................................48 
11.3 
Measurement of Study Drug Adherence ...........................................................48 
11.4 
Study Drug Accountability ................................................................................48 
11.5 
Prior and Concomitant Therapy ........................................................................49 
12 
Study Visits .......................................................................................... 50 
12.1 
Visit 1: Screening (≤30 days prior to Baseline [Day 1]): ..................................50 
12.2 
Masked Dose Escalation Phase .........................................................................51 
12.3 
Masked, Fixed Dose Phase ................................................................................53 
12.4 
Study Exit ..........................................................................................................55 
12.5 
Early Termination..............................................................................................56 
12.6 
Unscheduled Visits ............................................................................................56 
13 
Study Assessments ............................................................................... 57 
13.1 
Informed Consent ..............................................................................................57 
13.2 
Eligibility Assessment .......................................................................................57 
13.3 
Demographic Data .............................................................................................57 
13.4 
Medical, Surgical, and Ocular History ..............................................................57 
13.5 
Prior and Concomitant Therapy ........................................................................57 
13.6 
Pregnancy Testing .............................................................................................57 
13.7 
Abbreviated Physical Examinations ..................................................................58 
13.8 
Vital Signs .........................................................................................................58 
13.9 
12-Lead Electrocardiogram ...............................................................................58 
13.10 
Clinical Laboratory Evaluations ........................................................................58 
13.11 
Aqueous Humor Collection for Biomarkers .....................................................59 
13.12 
Visual Acuity .....................................................................................................59 


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13.13 
Slit-lamp Biomicroscopy ...................................................................................60 
13.14 
Intraocular Pressure ...........................................................................................60 
13.15 
Gonioscopy ........................................................................................................61 
13.16 
Dilated Ophthalmoscopy ...................................................................................61 
13.17 
Color Fundus Photography ................................................................................61 
13.18 
Spectral Domain Optical Coherence Tomography ...........................................61 
13.19 
Fluorescein Angiography ..................................................................................62 
13.20 
Retinal Oximetry Imaging .................................................................................62 
13.21 
Evaluation of Adverse Events ...........................................................................62 
14 
Data Monitoring Committee ................................................................ 68 
15 
Study Endpoints ................................................................................... 69 
15.1 
Primary Efficacy Endpoint ................................................................................69 
15.2 
Secondary Efficacy Endpoints ..........................................................................69 
16 
Statistical Analysis and Study Variables ............................................. 70 
17 
Data Handling and Quality Assurance ................................................ 72 
17.1 
Case Report Forms ............................................................................................72 
17.2 
Monitoring of the Study ....................................................................................72 
17.3 
Inspection of Records ........................................................................................72 
17.4 
Study Record Retention.....................................................................................73 
18 
Study Ethical Considerations ............................................................... 74 
18.1 
Ethical Conduct of the Study.............................................................................74 
18.2 
Informed Consent ..............................................................................................74 
18.3 
Institutional Review Board ................................................................................74 
19 
Administrative Considerations ............................................................ 76 
19.1 
Confidentiality ...................................................................................................76 
19.2 
Modification of the Protocol .............................................................................76 
19.3 
Protocol Deviations ...........................................................................................76 
19.4 
Study Reporting Requirements .........................................................................77 
19.5 
Financial Disclosure ..........................................................................................77 
19.6 
Financial Obligations ........................................................................................77 
19.7 
Investigator Documentation ..............................................................................77 


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19.8 
Clinical Trial Agreement ...................................................................................78 
19.9 
Policy for Publication and Presentation of Data ...............................................78 
20 
Investigator Agreement ....................................................................... 79 
21 
References ............................................................................................ 80 
22 
Appendices ........................................................................................... 82 
22.1 
Appendix A: Schedule of Events ......................................................................82 
22.2 
Appendix B:  Prohibited CYP2D6 Inhibitors and Inducers ..............................84 
22.3 
Appendix C:  ADA and WHO Diabetes Criteriac .............................................84 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Clinical Laboratory Assessments Performed During the Study ....59 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Emixustat inhibits the RPE65 isomerase in the visual cycle. ..........................26 
Figure 2 
T1 values represent Mn2+ movement through ion channels in emixustat-
treated rats. .......................................................................................................27 
Figure 3   
Effect of multidose treatment of emixustat on Mn2+ movement through 
ion channels. ....................................................................................................28 
Figure 4 
Oxygen consumption study in emixustat-treated rats. .....................................29 
Figure 5 
Dose-dependent reduction in neovascularization by emixustat in a 
mouse model of oxygen-induced retinopathy. .................................................31 
Figure 6 
Study Design Schema ......................................................................................35 
 


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5 
Glossary of Abbreviations and Definition of Terms 
ABBREVIATION 
DEFINITION 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCVA 
best corrected visual acuity 
βHCG 
ß-human chorionic gonadotropin 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRA  
clinical research associate 
CST 
central subfield thickness 
CTCAE 
common terminology criteria for adverse events 
CYP 
cytochrome P450 (eg, CYP2D6) 
DME 
diabetic macular edema 
ECG 
electrocardiogram 
eCRF 
electronic case report form(s) 
eGFR 
estimated glomerular filtration rate 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 
FDA 
Food and Drug Administration 
HbA1c 
glycosylated hemoglobin A1c 
ICF 
informed consent form 
ICH 
International Conference for Harmonisation 
IL 
interleukin (eg, IL-1, IL-2) 
IND 
Investigational New Drug (Application) 
INR 
international normalized ratio 
IOP 
intraocular pressure 
IP-10 
Interferon-gamma inducible protein 10  
IRB 
Institutional Review Board 
LL-BCVA 
low luminance best corrected visual acuity 
MCP-1 
monocyte chemotactic protein-1 
msec 
milliseconds 
NL-BCVA 
normal luminance best corrected visual acuity 
NV 
neovascularization 
PDGF 
platelet-derived growth factor 


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ABBREVIATION 
DEFINITION 
PDR 
proliferative diabetic retinopathy 
Pmin 
minimum oxygen pressure 
PO2 
partial oxygen pressure 
PRP 
panretinal photocoagulation 
PT 
prothrombin time 
QD 
once daily 
SAE 
serious adverse event 
SD 
standard deviation 
SD-OCT 
spectral domain optical coherence tomography 
T4 
thyroxine 
TGFβ-1 
transforming growth factor beta 1 
ULN 
upper limit of the normal range 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
 


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6 
Introduction 
6.1 
Background 
Diabetes mellitus is one of the most common endocrine disorders in the world; it affected 
roughly 6% of the global population in the year 2000, and it is estimated that it will affect 300 
million people by 2025(1). Diabetic retinopathy affects 28.5% of patients in the US adult 
diabetic population (2) and is the main cause of permanent vision loss in the US working 
population (3).  
Early stages of diabetic retinal pathology involve microaneurysms, hemorrhages and other 
disruptions in retinal circulation. This early, non-proliferative stage may be followed by 
proliferative diabetic retinopathy (PDR), characterized by the pathological formation of new 
retinal blood vessels. Despite progress in diagnostics and therapies, PDR, if untreated, may 
lead to a terminal stage of neovascularization (NV) that is characterized by the development of 
secondary neovascular glaucoma in a number of cases.  There is convincing scientific and 
clinical evidence that hypoxia is the driving force that mediates the development of retinal 
neovascularization (NV) in patients with diabetic retinopathy and other ischemic retinopathies 
(4-7). 
6.2 
Rationale for the Study 
Emixustat directly modulates the visual cycle, the biochemical pathway that restores the 
chromophore (11-cis retinal) needed for phototransduction. It targets the RPE65 protein, which 
functions as a retinol isomerase.  RPE65 converts all-trans retinyl esters to 11-cis retinol 
which, in turn, is converted to 11-cis retinal; 11-cis retinal is then again available for 
interaction with opsin and detection of light (Figure 1). In dark conditions (eg, while sleeping), 
phototransduction is inactive and photoreceptors consume large amounts of ATP and oxygen 
to fuel an ion pumping activity that is necessary to maintain electrochemical gradients across 
the outer segment membrane (4).  This ion pumping activity is referred to as the dark current.  
The dark current is reversed during light adaptation when light causes the conversion of the 
chromophore 11-cis retinal to all-trans retinal.  The chromophore dissociates from the opsin 
protein, producing apo-opsin – which activates the phototransduction machinery causing 
closure of ion channels and a decrease in retinal ATP and oxygen consumption by 40%–60%, 
relative to the dark adapted state (8).  


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Figure 1 
Emixustat inhibits the RPE65 isomerase in the visual cycle 
Emixustat decreases levels of visual chromophore in photoreceptors, which is expected to 
result in increased levels of free opsin (ie, apo-opsin).  Increased levels of apo-opsin have been 
shown to prevent complete dark adaptation through constitutive activation of rod 
phototransduction; this has been theorized to prevent hypoxia and preserve vasculature of the 
inner retina. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








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Levels of biomarkers including interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemo-
attractant protein-1(MCP-1), interferon gamma-inducible protein 10 (IP-10), transforming 
growth factor beta 1 (TGFβ-1), vascular endothelial growth factor (VEGF), platelet-derived 
growth factor AA (PDGF-AA), and interleukin-1β  have been shown to be elevated in the 
intraocular fluid of subjects with PDR (13-19).  The association of visual cycle modulation to 
the levels of biomarkers in the aqueous humor of subjects with PDR is not known. The 
Sponsor is proceeding with a Phase 2 study which will evaluate the effect of emixustat on this 
panel of biomarkers in aqueous humor. 




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will be returned to and held stable at the last tolerated dose; after week 4, all subjects will be 
held at a stable dose for the remainder of the study. 
 


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7 
Study Objectives 
7.1 
Primary Objective 
The primary objective of this study is to evaluate the effects of oral emixustat on aqueous 
humor biomarkers (interleukin [IL]-6, IL-8, interferon-gamma inducible protein [IP]-10, 
platelet-derived growth factor [PDGF]-AA, transforming growth factor [TGF]β-1, monocyte 
chemo-attractant protein [MCP]-1, IL-1β, and vascular endothelial growth factor [VEGF]) in 
subjects with PDR with or without diabetic macular edema (DME), from baseline to Day 85. 
7.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the effects of oral emixustat on: 
1. Change in area of retinal NV from baseline to Day 85 
2. Change in degree of vitreous hemorrhage from baseline to Day 85 
3. Change in degree of preretinal hemorrhage from baseline to Day 85 
4. Change in normal luminance best-corrected visual acuity (NL-BCVA) from baseline to 
Day 85 
5. Change in central subfield thickness (CST) as assessed by spectral domain optical 
coherence tomography (SD-OCT) from baseline to Day 85 in subjects with DME  
6. Change in retinal vessel oxygen saturation as measured by retinal oximetry imaging 
from baseline to Day 85 
7. Safety and tolerability compared to placebo when administered orally for 84 days 
7.3 
Exploratory Objectives 
Not applicable 


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8 
Investigational Plan 
8.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-masked, placebo-controlled study to evaluate the 
effects of emixustat in subjects with PDR. Subjects will be randomly assigned to one the 
following treatment arms in a 1:1 ratio: 
• Emixustat, up to 40 mg (step-up titration) 
• Placebo 
Subjects will take 4 tablets of study drug (emixustat or placebo) orally, QD, in the evening, for 
84 days. 
Emixustat (2.5, 5, or 10 mg) tablets or its placebo will be packaged in identical, tamper proof, 
blister packaging to maintain masking.  
During Week 1, subjects randomized to emixustat will receive 4 tablets (two placebo, two 
2.5 mg) per day for a 5 mg dose. During Week 2, subjects will receive 4 tablets (two placebo, 
two 5 mg) per day for a 10 mg dose. During Week 3, subjects will receive 4 tablets (two 
placebo, two 10 mg) per day for a 20 mg dose. During Weeks 4 through 12, subjects will 
receive four 10 mg tablets per day for a 40 mg dose. Subjects who do not tolerate dose 
escalations will be returned to and held stable at the last tolerated dose; after week 4, all 
subjects will be held at a stable dose for the remainder of the study.  
 
Subjects in the placebo group will undergo the same dosing regimen of 4 tablets, QD, with the 
placebo therapy. 
Aqueous humor collection for biomarkers will be conducted on Day 1 (Visit 2) and Day 85 
(Visit 8). Safety assessments throughout the study will include adverse events (AEs), NL-
BCVA, LL-BCVA, slit-lamp biomicroscopy, SD-OCT, intraocular pressure (IOP), dilated 
ophthalmoscopy, gonioscopy, physical examination findings, vital signs, electrocardiograms 
(ECGs), and clinical laboratory tests (blood chemistry, hematology, coagulation, urinalysis). 
The study design is presented schematically in Figure 6. 
 
 


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Figure 6 
Study Design Schema 
 
 
Subjects diagnosed with Type 1 or Type 2 diabetes mellitus 
with PDR, with or without DME 
Week 1 
5.0 mg 
(2 x 2.5 mg + 
2 placebo tablets) 
Screening (Day -1 to -30) 
Randomization (1:1)  
(Baseline/Day 1) 
Emixustat 
Weeks 4-12 
40.0 mg 
(4 x 10 mg 
tablets) 
Week 3 
20.0 mg 
(2 x 10 mg + 
2 placebo tablets) 
Week 2 
10.0 mg 
(2 x 5.0 mg + 
2 placebo tablets) 
Week 1 
0.0 mg 
4 placebo tablets 
Safety Assessments 
• AEs 
• NL-BCVA 
• LL-BCVA 
• slit-lamp 
biomicroscopy 
• SD-OCT 
• IOP 
• gonioscopy 
• dilated 
ophthalmoscopy 
• physical 
examination  
• vital signs 
• ECGs 
• clinical laboratory 
tests 
Day 1: Aqueous Humor 
(Biomarkers)  
Day 85: Aqueous Humor 
(Biomarkers)  
Placebo 
Week 2 
0.0 mg  
4 placebo tablets 
Week 3 
0.0 mg 
4 placebo tablets 
Weeks 4-12 
0.0 mg 
4 placebo tablets 


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8.2 
Number of Subjects 
Approximately 20 subjects will be enrolled in the study. 
8.3 
Study Sites 
This study will be conducted at up to 7 clinical sites in the United States. 
8.4 
Discussion of Study Design, Including the Choice of Control Groups 
Randomization and double-masking will be used to minimize bias in subject selection and the 
evaluation of subjects during the study. A placebo control is included to provide an objective 
comparison for the safety and efficacy of emixustat.  
Doses within the range previously assessed for safety have been selected, and a QD dosing 
regimen is based on the pharmacokinetic profile characterized in the Phase 1 program (Kubota 
2014). The step-wise dose escalation regimen and option to return to and hold subjects at a 
stable dose will allow for the evaluation of safety and tolerability of dosing durations longer 
than 2 weeks.  
The 84-day dosing period is expected to provide the opportunity to evaluate the effects of 
emixustat on PDR-associated aqueous humor biomarkers. 
 
8.5 
Efficacy Variables 
Efficacy variables will include: 
1. Aqueous humor concentration of the following biomarkers: IL-6, IL-8, interferon-
gamma inducible protein (IP)-10, PDGF-AA, TGFβ-1, MCP-1, IL-1β, and VEGF 
2. Area of retinal NV 
3. Degree of vitreous hemorrhage  
4. Degree of preretinal hemorrhage  
5. NL-BCVA 
6. CST as assessed by SD-OCT in subjects with DME 
7. Retinal vessel oxygen saturation 
8.6 
Pharmacodynamic Variables 
Cytokine assessments constitute the pharmacodynamic efficacy variables. 


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8.7 
Safety Variables 
Safety variables will include AEs, NL-BCVA, LL-BCVA, slit-lamp biomicroscopy, SD-OCT, 
IOP, gonioscopy, dilated ophthalmoscopy, physical examination findings, vital signs, ECGs, 
and clinical laboratory tests. Pregnancy tests will be conducted for women of childbearing 
potential. 


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9 
Study Population 
9.1 
Target Population 
The target population of this study is male or female subjects between the ages of 18 and 85 
years diagnosed with PDR, with or without DME. 
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: 
1. Able and willing to provide a written informed consent before undergoing any study-
related procedures.  
2. In the opinion of the investigator, the ability and willingness to return for all scheduled 
visits and perform all assessments.  
3. Males or females, ≥ 18 and ≤ 85 years of age at the Screening Visit.  
4. A documented diagnosis of type 1 or type 2 diabetes mellitus. Any one of the following 
will be sufficient evidence that diabetes is present: 
a. Current regular use of insulin for the treatment of diabetes 
b. Current regular use of an oral anti-hyperglycemia agent for the treatment of 
diabetes 
c. Documented diabetes by American Diabetes Association and/or World Health 
Organization (WHO) criteria (see Appendix C for definitions) 
5. The following ocular criteria for the study eye: 
a. Presence of PDR with or without DME for which, in the Investigator's 
judgment, interventional treatment can be safely deferred for at least 4 weeks 
after the Day 1 visit. 
b. No prior pan-retinal photocoagulation (PRP); defined as ≥ 500 burns placed 
previously outside the posterior pole. 
c. No intravitreal injection of an anti-VEGF agent in the 3 months prior to 
randomization (Day 1). 
d. No intravitreal or peri-bulbar injection of a corticosteroid in the 4 months prior 
to randomization (Day 1). 


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e. Early Treatment Diabetic Retinopathy Study (ETDRS) NL-BCVA letter score 
of ≥ 24 (approximate Snellen equivalent 20/320) on the day of randomization 
(Day 1). 
f. Media clarity, pupillary dilation, and subject cooperation sufficient to obtain 
adequate fundus photographs and SD-OCT. 
9.3 
Exclusion Criteria 
Subjects will be excluded from participation in the study if they meet any of the following 
criteria at screening and baseline (unless otherwise indicated): 
1. Any condition that, in the opinion of the investigator, would preclude participation in 
the study (eg, unstable medical status including blood pressure, cardiovascular disease, 
or glycemic control). 
2. Subjects with poor glycemic control, including those who initiated intensive insulin 
treatment (a pump or multiple daily injections) in the 4 months prior to Screening, or 
plan to do so in the next 4 months. 
3. Significant renal disease, defined as a history of chronic renal failure requiring dialysis 
or kidney transplant. 
4. Elevated blood pressure (defined as > 180/110; systolic above 180 or diastolic above 
110). Subjects with elevated blood pressure values, when attributable to specific 
circumstances (eg, missed medication, stress, etc.), may be retested on the same or later 
date, as appropriate (within the period between Screening and randomization (Day 1).  
5. History of myocardial infarction or other acute cardiac event requiring hospitalization, 
stroke, transient ischemic attack, or treatment for acute congestive heart failure within  
60 days prior to randomization. 
6. Previous participation (ie, randomization) in a study with emixustat. 
7. Participation (ie, randomization) in an investigational study of emixustat, or in another 
investigational trial within 30 days of the Screening Visit that involved treatment with 
any drug that has not received regulatory approval for the indication being studied.  
8. Known allergies to fluorescein sodium for injection in angiography, to emixustat, or to 
any excipients in the emixustat tablets (ie, silicified microcrystalline cellulose, pre-
gelatinized starch, colloidal silicon dioxide, or stearic acid).  
9. Prohibited medications:  


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a. Systemic use of a strong inducer of or a strong or moderate inhibitor of 
cytochrome P450 2D6 (CYP2D6; as listed in Appendix B) beginning 4 weeks 
prior to screening and throughout the duration of the study period. 
b. Anti-coagulant therapy (eg, heparins, warfarin, other oral anti-coagulants) 
beginning 14 days prior to screening and throughout the duration of the study.  
Anti-platelet therapy (eg, aspirin, clopidogrel) is allowed. 
10. History of systemic anti-VEGF or pro-VEGF treatment within 4 months prior to 
randomization or plan for such treatment during the course of the study. 
11. Any of the following laboratory abnormalities at screening: 
a. Aspartate transaminase (AST)/alanine transaminase (ALT) >3.0 x upper limit of 
normal (ULN) 
b. Total bilirubin >1.5 x ULN 
c. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 
d. Impaired coagulation: International Normalized Ratio (INR), prothrombin time 
(PT), or activated partial thromboplastin time (aPTT) >1.25 x ULN.   
e. Impaired hematologic function:  hemoglobin <9.0 g/dL;  
neutrophil count <1.6 x 109/L; or platelet count <100 x 109/L 
f. Any laboratory screening test that meets the abnormality criteria stated above 
can be repeated once within the period from screening to baseline.  
12. Any of the following ocular characteristics in the study eye: 
a. Tractional retinal detachment involving the macula. A tractional retinal 
detachment is not an exclusion if it is outside the posterior pole (not threatening 
the macula) and, in the Investigator’s opinion, is not considered a 
contraindication to deferring PRP, anti-VEGF therapy, or surgical intervention. 
b. Exam evidence of NV of the angle (NV of the iris alone is not an exclusion if it 
does not preclude deferring PRP or anti-VEGF therapy) 
c. A decrease in BCVA due to causes other than diabetic retinopathy (eg, foveal 
atrophy, pigment abnormalities, dense sub-foveal hard exudates, previous 
vitreoretinal surgery, non-retinal condition, substantial cataract, or macular 
ischemia) in the Investigator’s opinion. 


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d. An ocular condition (other than diabetic retinopathy) that, in the opinion of the 
Investigator, might alter visual acuity during the course of the study (eg, retinal 
vein or artery occlusion, uveitis or other ocular inflammatory disease, 
neovascular glaucoma, etc.). A vitreous or preretinal hemorrhage is not an 
exclusion if it is out of the visual axis and, in the Investigator’s judgement, is 
not having any effect on visual acuity. 
e. History of major ocular surgery (including vitrectomy, cataract extraction, 
scleral buckle, any intraocular surgery, etc.) within 3 months prior to the 
Screening Visit or anticipated to occur within during the course of the study. 
f. History of YAG capsulotomy performed within 2 months prior to 
randomization (Day 1) or anticipated during the course of the study. 
g. Aphakia  
h. Uncontrolled glaucoma (in the Investigator’s judgement). 
i. Exam evidence of periocular or ocular infection (eg, blepharitis, chalazion, or 
conjunctivitis). 
a. Implantation of any of the following intraocular corticosteroid implants in the 
timeframe indicated: 
i. Fuocinolone acetonide (Iluvien®), in the 30 months prior to 
randomization (Day 1) 
ii. Dexamethasone (Ozurdex®), in the 4 months prior to randomization 
iii. Any other corticosteroid implant, in the 4 months prior to randomization  
j. Macular edema due to anything other than DME (eg, post ocular surgery, age-
related macular degeneration, uveitis, retinal vein occlusion, or drug toxicity) 
13. Change in a systemic prescription medication or a systemic medication newly 
prescribed within 30 days prior to screening and between screening and baseline or 
anticipated during the course of the study. 
14. Presence of other disease, physical examination finding, or clinical laboratory finding 
that, in the opinion of the Investigator, gives reasonable suspicion of a disease or 
condition which contraindicates the use of an investigational drug, places the subject at 
risk by participating in the study, or confounds the ability to interpret data from the 
study.  


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15. Current or history of cancer (except for adequately treated basal cell or squamous cell 
carcinoma of the skin) within 1 year of screening. 
16. ECG 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. 
17. Female subjects who are pregnant or lactating. 
18. 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 following the completion of the study. Medically accepted methods of 
birth control include abstinence, hormonal contraceptives, non-hormonal intrauterine 
contraceptive device with spermicide, condom with spermicide, contraceptive sponge 
with spermicide, diaphragm with spermicide, or cervical cap with spermicide. 
19. 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 completion of the study. 
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 investigator should select the study eye as the eye with the least 
potential to require PRP, anti-VEGF therapy, or local corticosteroids during the study, in 
his/her opinion. 
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 consist of 5 digits: a 2-digit site number and a consecutive 3-digit subject 
screening number. 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 
Visits 1 and 2, they will be enrolled and randomly assigned to study treatment through the use 
of an interactive web response system (IWRS). 


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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: 
• AEs 
• 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 reason(s) 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).  Whenever possible, all subjects who withdraw from the study 
prematurely will undergo assessments listed for the Early Termination visit. 
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. 


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10 
Randomization and Masking 
10.1 
Randomization 
At Baseline (Day 1), eligible subjects will be randomized in a 1:1 ratio to 1 of 2 treatment 
arms: 
• Emixustat, up to 40 mg (step-up titration) 
• Placebo 
Randomization will be stratified by DME status (DME vs. no DME) and will occur in a 
masked fashion according to a randomization scheme generated by an interactive web response 
system (IWRS). A randomization number will be assigned to each subject at this time. The 
screening number which was assigned when the subject enrolled will be the subject ID number 
for the remainder of the study 
10.2 
Masking 
Study subjects, Investigators and their staff, and Sponsor personnel involved with the conduct 
and monitoring of the study will be masked to the identity of treatment until after the final 
database is locked. Emixustat and placebo will be identical appearing tablets, and each 
treatment will be packaged in identical, tamper-proof, blister packaging to maintain masking. 
All subjects will receive masked replacement (resupply) kits provided through the IWRS. In 
order to maintain masking, subjects randomized to the placebo arm will be mock-titrated on the 
same schedule as those in the step-up titration arm.  
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 a serious adverse event (SAE) is assessed as unexpected and related to study drug, and meets 
the requirement for expedited regulatory submission, the Sponsor’s Drug Safety department 
will unmask the treatment assignment for the individual subject, if warranted. Expedited 


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reports will be submitted to regulatory authorities in accordance with applicable regulations. 
Expedited reports will also be distributed to Investigators without revealing the treatment 
assignment and will be submitted to IRB in accordance with institutional guidelines.  
If emergency unmasking is required for any reason, the subject will be withdrawn from the 
study. 


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11 
Study Treatments 
11.1 
Drug Dosage and Administration 
 
Emixustat Hydrochloride 
Study drug will be taken orally, QD, in the evening for 84 days. Subjects will receive 4 tablets 
per day as follows:  
• Week 1 = 5 mg emixustat/day – two 2.5 mg tablets plus two placebo tablets 
• Week 2 = 10 mg emixustat/day – two 5 mg tablets plus two placebo tablets 
• Week 3 = 20 mg emixustat/day – two 10 mg tablets plus two placebo tablets 
• Week 4 through Week 12 = 40 mg emixustat/day = four 10 mg tablets 
 
Comparative Treatment (Placebo) 
Subjects in the placebo group will undergo the same dosing regimen as the active treatment 
group with subjects taking 4 placebo tablets orally, QD, in the evening for 84 days. The 
placebo tablets will be identical in appearance to the emixustat tablets but with only inactive 
ingredients.   
 
Dose Reduction 
Subjects who do not tolerate dose escalations will be returned to and held stable at the last 
tolerated dose; after week 4, all subjects will be held at a stable dose for the remainder of the 
study.  Dose reduction is available for subjects who do not tolerate dose escalations due to AEs 
that in the opinion of the investigator would otherwise lead to discontinuation of study drug.  
Dose reduction may be undertaken only once and is only available at Visit 4, Visit 5, or Visit 6. 
 
Rescue Therapy 
Rescue Treatment Criteria for PDR 
All subjects will be eligible for PRP or anti-VEGF therapy for PDR in the study eye as of Day 
29 (Visit 6) of the study if the following criterion is met: 
• There is new NV or growth of NV of the retina, disc, angle, OR iris such that the NV is 
greater in extent than at Day 1 (Visit 2/Baseline). 
 


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Rescue Treatment Criteria for DME 
All subjects will be eligible for therapy for DME in the study eye as of Day 29 (Visit 6) of the 
study if either of the following criteria are met: 
a. Development or worsening of DME as illustrated by an increase in central retinal 
thickness of ≥100 microns from any previous visit (as measured by the Investigator) 
b. A BCVA decrease of ≥10 letters from any previous visit that is deemed secondary to 
DME. 
Subjects for whom it is determined that treatment with PRP, anti-VEGF therapy, or local 
corticosteroids in the study eye is necessary will discontinue study drug, be discontinued from 
the study, and undergo Early Termination assessments prior to any of these therapies. 
PRP, anti-VEGF agent therapy, focal laser therapy, or local corticosteroid therapy in the non-
study eye is allowed at any time, at the Investigator’s discretion. 
11.2 
Supply, Packaging, Labeling, and Storage 
Emixustat (2.5, 5, or 10 mg) tablets and placebo tablets will be packaged in identical, tamper-
proof, blister packaging to maintain masking. 
11.3 
Measurement of Study Drug Adherence 
Study drug will be taken orally, QD, in the evening, for 84 days. At each study visit, the 
subject will be queried regarding compliance with the treatment regimen. 
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 can be returned to the Sponsor or designee 
according to applicable state and federal regulations. 
If study drug is returned by the site, it must be accompanied by the 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 


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should facilitate the return of unused study drug and opened, empty blister packaging from 
used study drug. 
If study drug is authorized by the Sponsor to be destroyed at the site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the appropriate disposal.  
Written authorization should be issued by the Sponsor; procedures for proper disposal should 
be established according to applicable regulations, guidelines and procedures.  Appropriate 
records of the disposal should be maintained. 
11.5 
Prior and Concomitant Therapy 
In addition to the exclusion criteria, the following are excluded during the course of the study: 
• Systemic use of a strong inducer of or a strong or moderate inhibitor of CYP2D6 (as 
listed in Appendix B) 
• Anti-coagulant therapy (eg, heparins, warfarin, other oral anti-coagulants).  Anti-
platelet therapy (eg, aspirin, clopidogrel) is allowed. 
• Systemic anti-VEGF or pro-VEGF treatment  
If elective, urgent, or emergency surgery is required at any time between randomization and 
Day 85, 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 Appendix B) 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 Appendix A.  A detailed accounting of assessments 
performed at each study visit is presented below. 
The scheduled visits include Screening (within 30 days prior to baseline), Baseline (Day 1), 
and days 8, 15, 22, and 29 (each ±1 day) and days 57 and 85 (each ±5 days). The Day 85 visit 
will be one day after the last drug/placebo treatment. The Study Exit visit will be performed 30 
days (±5 days) after the last dose of study drug. 
12.1 
Visit 1: Screening (≤30 days prior to Baseline [Day 1]): 
The following procedures will be performed at Visit 1, Screening (≤30 days prior to 
Baseline [Day 1]): 
• Explain the purpose and conduct of the study visits to the subjects, answer the subject’s 
questions, and obtain written informed consent 
• Review inclusion/exclusion criteria 
• Obtain demographic data 
• Obtain medical, surgical, and ocular history 
• Review previous and concomitant medications 
• Perform abbreviated physical exam including height and weight 
• Obtain 12-lead ECG  
• Obtain vital signs 
• Blood sample for serum pregnancy test for women of childbearing potential 
• Blood samples for clinical chemistry, hematology (including glycosylated 
hemoglobin A1c [HbA1c]), and coagulation. (Note: Any laboratory screening 
test that meets the abnormality criteria stated in Exclusion Criterion No. 10 
[Section 9.3, Exclusion Criteria] can be repeated once within the 30 day period 
from screening to baseline.)   
• Urinalysis 
• The following ophthalmic procedures will be performed: 
 NL-BCVA 
 Slit-lamp biomicroscopy 


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 IOP 
 Gonioscopy 
 Dilated ophthalmoscopy 
 SD-OCT 
• AEs 
• Schedule subject to return for Baseline Visit (Day 1) within the specified window of 
time. 
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. 
 
12.2 
Masked Dose Escalation Phase 
 
Visit 2: Baseline (Day 1) 
The following procedures will be performed at Visit 2, Baseline (Day 1): 
• Review inclusion/exclusion criteria 
• Review and update medical, surgical, and ocular history 
• Review concomitant medications 
• Randomization 
• Obtain vital signs 
• Urine pregnancy test (for women of childbearing potential) 
• Blood sample for clinical chemistry, hematology, and coagulation. If screening 
laboratories were performed ≤14 days prior to Baseline (Day 1), these tests do not have 
to be repeated. 
• Urinalysis.   If screening laboratories were performed ≤14 days prior to Baseline 
(Day 1), this test does not have to be repeated. 
• The following ophthalmic procedures will be performed: 
 NL-BCVA 
 LL-BCVA 
 Slit-lamp bio-microscopy 


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 IOP 
 Gonioscopy 
 Dilated ophthalmoscopy 
 FA 
 Color fundus photographs  
 SD-OCT  
 Retinal oximetry imaging (may be performed at selected sites) 
• Aqueous humor collection (50 μl) from the study eye by paracentesis and shipped the 
same day on dry ice.  
• AEs 
• Dispense 1 week supply of masked study drug (5 mg emixustat or placebo) for subjects 
to self-administer 4 tablets (orally, QD, in the evening) for 7 days.  
• Schedule subject to return for Visit 3 (Day 8 ± 1 day). 
 
Visit 3 (Day 8 ± 1 day) 
• AEs 
• Review concomitant medications 
• Collect blister pack of study drug and review compliance 
• Dispense a 1 week supply of double the dose received at the Day 1 visit (10 mg 
emixustat or placebo) for self-administration of 4 tablets (orally, QD, in the evening) 
for 7 days. 
 
Visit 4 (Day 15 ± 1 day) 
• AEs 
• Review concomitant medications 
• Collect blister pack of study drug and review compliance 
• Dispense a 1 week supply of double the dose received at the Day 8 visit (20 mg 
emixustat or placebo) for self-administration of 4 tablets (orally, QD, in the evening) 
for 7 days. 


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Note: Dose reduction is available for subjects who do not tolerate dose escalations due to 
AEs that in the opinion of the investigator would otherwise lead to discontinuation of study 
drug.  The subject will be returned to and held stable at the last tolerated dose. 
 
Visit 5 (Day 22 ± 1 day) 
• AEs 
• Review concomitant medications 
• Collect blister pack of study drug and review compliance 
• Dispense a 1 week supply of double the dose received at the Day 15 visit (40 mg 
emixustat or placebo) for self-administration of 4 tablets (orally, QD, in the evening) 
for 7 days. 
Note: Dose reduction is available for subjects who do not tolerate dose escalations due to 
AEs that in the opinion of the investigator would otherwise lead to discontinuation of study 
drug.  The subject will be returned to and held stable at the last tolerated dose. 
12.3 
Masked, Fixed Dose Phase 
 
Visit 6 (Day 29 ± 1 day) 
• Urine pregnancy test (for women of childbearing potential) 
• Review concomitant medications  
• The following ophthalmic procedures will be performed: 
 NL-BCVA 
 Slit-lamp biomicroscopy 
 IOP 
 Dilated ophthalmoscopy 
 SD-OCT 
 Retinal oximetry imaging (may be performed at selected sites)  
• AEs 
• Collect blister pack of study drug and review compliance 


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• Dispense a 4 week supply of drug (40 mg emixustat or the last tolerated emixustat dose; 
or placebo), to be dispensed by self-administration of 4 tablets (orally, QD, in the 
evening) for 28 days. 
Note: Dose reduction is available for subjects who do not tolerate dose escalations due to 
AEs that in the opinion of the investigator would otherwise lead to discontinuation of study 
drug.  The subject will be returned to and held stable at the last tolerated dose. 
 
Visit 7 (Day 57 ± 5 days) 
• Urine pregnancy test (for women of childbearing potential)  
• Review concomitant medications 
• The following ophthalmic procedures will be performed: 
 NL-BCVA 
 Slit-lamp biomicroscopy 
 IOP 
 Dilated ophthalmoscopy 
 SD-OCT 
 Retinal oximetry imaging (may be performed at selected sites)  
• AEs 
• Collect blister packs of study drug and review compliance 
• Dispense a 4 week supply of drug (40 mg emixustat or the last tolerated emixustat dose; 
or placebo), to be dispensed by self-administration of 4 tablets (orally, QD, in the 
evening) for 28 days. 
 
Visit 8 (Day 85 ± 5 days) 
• Review concomitant medications 
• Collect blister packs of study drug and review compliance 
• Urine pregnancy test (for women of childbearing potential) 
• Physical exam including weight 
• Vital signs 
• Blood samples for clinical chemistry, hematology (including HbA1c), and coagulation 


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• Urinalysis 
• 12-lead ECG 
• The following ophthalmic procedures will be performed: 
 
NL-BCVA 
 
LL-BCVA 
 
Slit-lamp biomicroscopy 
 
IOP 
 
Gonioscopy 
 
Dilated ophthalmoscopy 
 
FA 
 
Color fundus photography 
 SD-OCT  
 Retinal oximetry imaging (may be performed at selected sites) 
• Aqueous humor collection (50 μl) from the study eye by paracentesis and shipped the 
same day on dry ice. 
• AEs 
12.4 
Study Exit 
A Study Exit visit will be performed 30 days (± 5 days) after the last dose of study drug.  
• Review concomitant medications 
• Urine pregnancy test (for women of childbearing potential) 
• The following ophthalmic procedures will be performed: 
 
NL-BCVA 
 
Slit-lamp biomicroscopy 
 
IOP 
 
Dilated ophthalmoscopy 
 
SD-OCT  


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12.5 
Early Termination 
Subjects who discontinue from the study early will undergo an Early Termination visit where 
all Day 85 visit assessments will be performed 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.  Subjects who have received study drug <21 days will not 
undergo collection of an aqueous humor sample at the Early Termination visit.  If the Early 
Termination visit occurs ≥25 days after last study drug dose, the Early Termination and Study 
Exit visits may be combined. 
12.6 
Unscheduled Visits 
Unscheduled visits may be necessary due to AEs or 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. 


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13 
Study Assessments 
This section describes the study assessment procedures.  For timing of study assessments, see 
the Schedule of Events (Appendix A).  For full details on each study assessment, refer to the 
Study Manual. 
13.1 
Informed Consent 
At Visit 1 (Screening, within 30 days prior to Baseline [Day 1]), 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 Visit 1 (Screening [Day -30 to Day -1], within 30 days prior to Baseline [Day 1]), each 
inclusion and exclusion criterion must be checked for each subject, as well as restricted and 
prohibited prior and concomitant therapy.  At Baseline (Visit 2/Day 1), eligibility requirements 
must be reviewed to determine if the subject is still eligible to continue in the study. 
13.3 
Demographic Data 
Demographic data, including age, gender, 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 (Day 
-30 to Day -1) and updated at Baseline (Day 1), 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 (see Section 11.5) will be assessed at Baseline 
(Visit 2/Day 1).  Concomitant therapies will be collected and recorded throughout the study. 
13.6 
Pregnancy Testing 
A serum pregnancy test will be conducted at the Screening visit (Day -30 to Day -1) and a 
urine pregnancy test will be conducted at Baseline (Visit 2/Day 1), Visit 6/Day 29 (± 1 day), 
Visit 7/Day 57 (± 5 days), and Visit 8/Day 85 (± 5 days; Study Exit) for women of 
childbearing potential. 


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13.7 
Abbreviated Physical Examinations 
Abbreviated physical examination, including a review of body systems and height and weight, 
will be performed by qualified study personnel. Height will only be recorded at the Screening 
Visit. Abnormal findings will be recorded. 
13.8 
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 position for at least 
5 minutes. 
13.9 
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.  ECGs will be read by the Investigator or other 
qualified designee. 
13.10 
Clinical Laboratory Evaluations 
The laboratory assessments listed in (Table 1) are to be performed according to the Schedule of 
Events (Appendix A). 
The investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study on the AE CRF.  All laboratory results 
must be reviewed prior to the next study visit to evaluate the subject’s safety for continued 
treatment.  With the exception of the urine pregnancy test and urinalysis, all laboratory 
assessments will be performed by a central laboratory. 
 


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Table 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 
estimated glomerular filtration rate (eGFR, by the Modification 
of Diet in Renal Disease Study equation) 
Hematology 
Hematocrit, hemoglobin, red blood cell count, platelet count, 
white blood cell count with automated differential (% and 
absolute count), and HbA1c 
Urinalysis 
Routine urinalysis (ie, dipstick) without microscopic 
examination 
Coagulation 
Prothrombin time (PT), international normalized ratio (INR), 
fibrinogen, and activated partial thromboplastin time (aPTT) 
Pregnancy a (serum 
at Screening, urine at 
each monthly visitb) 
ß-human chorionic gonadotropin 
a Women of childbearing potential only 
b Urine pregnancy testing will be conducted at Visit 2, Visit 6, Visit 7, Visit 8, and Visit 9 (Study Exit). 
 
13.11 
Aqueous Humor Collection for Biomarkers 
A 50 μl sample of aqueous humor will be collected from the study eye by paracentesis and 
shipped the same day on dry ice. 
13.12 
Visual Acuity 
Best-corrected visual acuity (BCVA) will be measured using the ETDRS retro-illuminated 
chart, the ETDRS electronic visual acuity (ETDRS-EVA) system, or the standard ETDRS wall 
chart in normal luminance lighting (NL-BCVA).  NL-BCVA will be recorded as total letter 
score in each eye. 


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Low luminance BCVA (LL-BCVA) will be measured after BCVA is measured in normal 
luminance.  A 2.0 log unit neutral density filter (ie, a filter that lowers luminance by 100 times, 
such as a Kodak Wratten filter, Rochester, NY), provided by the Sponsor, will be placed over 
the best correction for each eye in order to perform LL-BCVA. 
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. 
Detailed instructions for obtaining BCVA will be provided in a study-specific BCVA protocol. 
13.13 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed 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 described. 
13.14 
Intraocular Pressure 
IOP 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. 
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. 


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13.15 
Gonioscopy 
The anterior chamber angle will be assessed for degree of openness and NV with gonioscopy at 
Visits 1, 2, and 8.  Gonioscopy may be performed at any other visit, based on the Investigator’s 
clinical judgement. 
13.16 
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 described. 
13.17 
Color Fundus Photography 
Color fundus photographs (both eyes, 9 fields) will be performed to assess lesion 
characteristics of each eye for all subjects.  Photographs will be transmitted to and evaluated by 
the central reading center. 
Color fundus photographs will be obtained using a fundus camera which has been certified by 
the central reading center.  The study personnel who perform fundus photography will be 
trained and certified by the central reading center prior to enrollment of subjects. 
Detailed instructions for imaging and image transfer will be provided in the study-specific 
Image Acquisition and Submission Protocol. 
13.18 
Spectral Domain Optical Coherence Tomography 
SD-OCT will be performed to assess lesion characteristics and retinal structure of each eye for 
all subjects.  For SD-OCT, Heidelberg Spectralis models must be used.  Images will be 
evaluated by the Investigator.  The images will also be transmitted to and evaluated by the 
central reading center. 
The study personnel who perform SD-OCT will be trained and certified by the central reading 
center prior to enrollment of subjects. 


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Detailed instructions for imaging and image transfer will be provided in the study-specific 
Image Acquisition and Submission Protocol 
13.19 
Fluorescein Angiography 
Fluorescein angiography (FA; both eyes, 9 fields) will be performed to examine the circulation 
of the retina on each eye for all subjects.  Images will be evaluated by the Investigator.  Images 
will also be transmitted to the central reading center.  
The study personnel who perform FA will be trained and certified by the central reading center 
prior to enrollment of subjects. 
Detailed instructions for imaging and image transfer will be provided in the study-specific 
Image Acquisition and Submission Protocol 
13.20 
Retinal Oximetry Imaging 
Non-invasive retinal oximetry imaging may be performed at selected sites.  If obtained, images 
will be transmitted to and evaluated by the central reading center. 
The study personnel who perform retinal oximetry imaging will be trained and certified by the 
central reading center prior to enrollment of subjects. 
13.21 
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 adverse event 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”). 


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• 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. 
• 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 an 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 13.21.4. 
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 Adverse Event 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.  
Hospitalization for surgery planned before study entry is not considered an SAE. 
• 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 


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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. 
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; 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. 


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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. 
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 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 female partner of a male subject during study participation or within 90 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. 


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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. 
All abnormal pregnancy outcomes and/or any AE for the child or fetus (including miscarriage) 
will be recorded on the AE eCRF and SAE form.  The associated SAE form will be sent to and 
followed up by the Sponsor according to the procedure described in Section 13.21.2. 
An AE eCRF and/or SAE form, as appropriate, will be completed for subjects who are 
maternal to the child or fetus and if the subject sustains an AE.  The SAE form will be sent to 
the Sponsor in accordance with Section 13.21.2. 
 
Overdose 
Overdose is defined as any dose higher than the defined or prescribed dose of study drug.  
Occurrences of overdose leading to AEs 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 13.21.2. 
 
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. 
 
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.  


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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 
No involvement of an Independent Data Monitoring Committee is planned.  A Safety Review 
Team consisting of Sponsor staff and/or consultants will periodically review masked safety 
data. 


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15 
Study Endpoints 
15.1 
Primary Efficacy Endpoint 
The primary study endpoints are the change in aqueous humor concentration of eight 
biomarkers (IL-6, IL-8, IP-10, PDGF-AA, TGFβ-1, MCP-1 and IL-1β, and VEGF) from 
baseline (Day 1) to Day 85, the conclusion of an 84-day course of study drug. Analysis will 
include both absolute change and percent change from Baseline (Visit 2/Day 1) to Day 85 
(Visit 8/Study Exit).    
15.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will include: 
1. Change in area of retinal NV from baseline to Day 85, as assessed by the central 
reading center from color fundus photographs 
2. Change in degree of vitreous hemorrhage from baseline to Day 85, as assessed by the 
central reading center from color fundus photographs 
3. Change in degree of preretinal hemorrhage from baseline to Day 85, as assessed by the 
central reading center from color fundus photographs 
4. Change in NL-BCVA from baseline to Day 85 
5. Change in CST from baseline to Day 85, as assessed by the central reading center from 
SD-OCT, in subjects with DME 
6. Change in retinal vessel oxygen saturation from baseline to Day 85, as assessed by the 
central reading center from retinal oximetry imaging 
 


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16 
Statistical Analysis and Study Variables 
Eight subjects per arm yields 80% power to detect a difference between emixustat and placebo 
in each aqueous humor biomarker, assuming an effect size of 1.31, using a two-sample t-test 
and a two-sided alpha level of 0.10. To account for potential early termination subjects, 2 
additional subjects per treatment arm, for a total of 10 subjects per arm, will be enrolled. 
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 (SD), median, minimum and maximum), and 
categorical variables will be summarized using the count and percentage of subjects in each 
category. 
Primary and secondary endpoints will be summarized using standard quantitative (sample size, 
mean, SD, median, minimum, maximum, and 90% and 95% t-distribution confidence intervals 
[CI] around the mean) and qualitative (frequency counts,  percentages, and exact 90% and 95% 
CIs around the percentages) summary statistics and assessed using two-sided 90% and 95% t-
distribution CIs and two-sided, two-sample t-tests around the differences between treatment 
groups for quantitative measures.  For the assessment of changes from baseline in aqueous 
humor concentration of the 8 biomarkers, both absolute and percent changes will be analyzed. 
Additionally for quantitative measures, 1-sample t-tests will be completed on the change from 
baseline values within a treatment group.  Qualitative measures will be analyzed by exact 
McNemar’s test for changes within a treatment group and Fisher’s Exact Test for differences 
between treatment groups.  Differences in proportions and 90% and 95% CIs will also be 
presented for comparisons between treatment groups for qualitative variables.   
The assessment of safety will be based on the summaries of ocular and non-ocular AEs, NL-
BCVA, LL-BCVA, ophthalmic examination findings (slit lamp biomicroscopy, dilated 
ophthalmoscopy, IOP, gonioscopy), SD-OCT, vital signs, physical examination findings, 
ECGs, and clinical laboratory values.  Subjects will be summarized in the group according to 
the treatment received, and all subjects receiving emixustat will be combined into one group. 
AEs 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 two randomized treatment arms. 


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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. 
 


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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. 
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 Conference 
for Harmonisation (ICH) guideline E6 (R1):  Good Clinical Practice:  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. 
The Sponsor will review eCRF data and perform electronic edit checks on the data. 


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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. 


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18 
Study Ethical Considerations 
18.1 
Ethical Conduct of the Study 
The Investigator agrees that the study will be conducted according to the Good Clinical 
Practice 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, 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 and/or his/her legal guardian will 
be given a full explanation of the nature of the study and the action of the study drug.  The 
subject/legal guardian will be informed that participation is voluntary and that they can 
withdraw from the study at any time.  The subject/legal guardian will be allowed to read the 
approved ICF.  Once the Investigator is assured that the subject/legal guardian agrees to 
participate in the study, the subject/legal guardian 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 and/or legal 
guardian.  The original shall be maintained in the subject’s medical records at the site. 
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 or the subject’s legal guardian.  Documentation of all IRB approvals 


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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 
• 
ICF 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 


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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 (or the subject’s guardian), 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 IRB and approved 
prior to subjects being enrolled into an amended protocol. 
19.3 
Protocol Deviations 
A protocol deviation occurs when the Investigator or subject has failed to adhere to significant 
protocol requirements.  All important 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 an excluded concomitant treatment 
Other protocol deviations to be considered include nonadherence to the protocol that results in 
a significant additional risk to the subject. 


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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.  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 time line 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. 
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) 


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• 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 or legal guardians 
• IRB approval of the Investigator, protocol, and 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. 
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 Multicenter, Randomized, 
Double-Masked, Placebo-Controlled, Pilot Study to Evaluate Effects of Emixustat 
Hydrochloride on Aqueous Humor Biomarkers Associated with Proliferative Diabetic 
Retinopathy”, and in accordance with generally accepted standards of Good Clinical Practice, 
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 section 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. Adeghate E, Schattner P, Dunn E. (2006). An update on the etiology and epidemiology 
of diabetes mellitus. Ann N Y Acad Sci. 1084:1-29. 
2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United 
States, 2005-2008. JAMA. 2010 Aug 11;304(6):649. 
3. Klein, BE. (2007). Overview of epidemiologic studies of diabetic retinopathy. 
Ophthalmic Epidemiol. 14(4):179-183. 
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22.2 
Appendix B:  Prohibited CYP2D6 Inhibitors and Inducers 
The medications listed in the table below are the systemic CYP2D6 inhibitors and inducers 
prohibited during the study or within 4 weeks prior to screening. 
Prohibited CYP2D6 Inhibitors and Inducers 
Inhibitors 
• Amiodarone 
• Dronedarone 
• Cinacalcet 
• Duloxetine 
• Terbinafine 
• Bupropion 
• Fluoxetine 
• Paroxetine 
• Quinidine 
Inducers: No medications currently meet this criterion 
 
 
22.3 
Appendix C:  ADA and WHO Diabetes Criteriac 
ADA Criteria for Diabetes Diagnosis 
A1C ≥6.5%a, b 
Perform in lab using NGSP-certified method and standardized to DCCT assay 
Or 
FPG ≥126 mg/dL (7.0 mmol/L)b 
Fasting defined as no caloric intake for ≥8 hrs 
Or 
2-hr PG ≥200 mg/dL (11.1 mmol/L) during OGTT (75-g)b  
Performed as described by the WHO, using glucose load containing the equlivalent of 75g 
anhydrous glucose dissolved in water 
Or 
Random PG ≥200 mg/dL (11.1 mmol/L) 
In persons with symptoms of hyperglycemia or hyperglycemic crisis 
a Test should be performed in a lab using a NGSP-certified method and standardized to the Diabetes Control 
and Complications Trial (DCCT) assay  
b In the absence of unequivocal hyperglycemia results should be confirmed using repeat testing 
c Source: http://www.ndei.org/dsl/newslide.aspx?Slideid=3024 
 


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WHO Criteria for Diabetes Diagnosisa 
FPG ≥ 7.0mmol/l (126mg/dl) 
Or 
2-hr PG ≥11.1mmol/l (200mg/dl) 
ahttp://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf