Conditions: Age-Related Macular Degeneration (AMD) Macular Degeneration Exudative Age-related Macular Degeneration AMD Macular Degeneration, Age-related, 10 Eye Diseases Retinal Degeneration Retinal Diseases
Keywords: Vascular Endothelial Growth Factor (VEGF) Platelet Derived Growth Factor (PDGF) AMD
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 157
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of X-82 in the treatment of vision loss due to wet AMD.

Detailed description:
Subjects will be randomized in a 1:1:1:1 ratio to the following dose groups:

* X-82 50 mg plus ivt anti-VEGF prn
* X-82 100 mg plus ivt anti-VEGF prn
* X-82 200 mg plus ivt anti-VEGF prn
* Placebo plus ivt anti-VEGF prn

Subjects will be treated for a total of 52 weeks with one of three doses of X-82 or placebo.

Primary Efficacy Outcome:

The primary efficacy outcome is the change in visual acuity score from Day -1 to 52 Weeks after randomization.

Safety Outcomes:

Systemic and ocular safety will be evaluate by assessing ECG, laboratory analyses, adverse events and serious adverse events.

Approximately 132 subjects will be randomized into one of the four arms (33 subjects per dose group).

Arms:
arm 1: Subject will administer one 50 mg tablet of X-82 and one placebo tablet once daily. Subjects will be assessed for the need for retreatment with ivt anti-VEGF therapy at each visit. arm 2: Subject will administer two 50 mg tablets of X-82 once daily. Subjects will be assessed for the need for retreatment with ivt anti-VEGF therapy at each visit. arm 3: Subject will administer two 100 mg tablets of X-82 once daily. Subjects will be assessed for the need for retreatment with ivt anti-VEGF therapy at each visit. arm 4: Subject will administer two placebo tablets once daily. Subjects will be assessed for the need for retreatment with ivt anti-VEGF therapy at each visit.

Interventions: intervention 1: X-82 intervention 2: Anti-VEGF intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
 
 
X-82 to treat Age-related Macular Degeneration 
 
 
PROTOCOL X82-OPH-201 
 
A Randomized, Double-Masked, Placebo-Controlled, Dose-
Finding, Non-Inferiority Study of X-82 plus prn ivt anti-
VEGF  compared to prn ivt anti-VEGF monotherapy in 
neovascular AMD  
 
 
Protocol Version: 12 September 2017 
Version 10 
EudraCT Number 2015-001632-38 
 
TYROGENEX, INC. 
 
 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Tyrogenex, Inc., except to the extent necessary to obtain informed 
consent from persons involved in the clinical study or their legal guardians, or for discussions 
with local regulatory authorities, institutional review boards (IRB), or persons participating in the 
conduct of the trial. 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
PROTOCOL SUMMARY 
Protocol Number
X82-OPH-201 
Title 
A randomized, double-masked, placebo-controlled, dose-finding, 
non-inferiority study of X-82 plus prn ivt anti-VEGF  compared 
to prn ivt anti-VEGF monotherapy in neovascular AMD  
Sponsor 
Tyrogenex, Inc. 
Regulatory Status 
Phase 2b 
Objectives 
The objective is to evaluate the safety and efficacy of X-82 at 
three doses as determined by a comparison of the mean visual 
acuity at 52 weeks in subjects with neovascular AMD 
Study Design 
Double-masked, placebo-controlled multicenter clinical trial in 
which subjects will be randomized (1:1:1:1) with one of three 
doses of X-82 plus ivt anti-VEGF  prn versus placebo plus ivt 
anti-VEGF prn.  
Study Population 
Subjects with neovascular AMD 
Number of Subjects 
Approximately 132 subjects 
Number of Groups/Arms 
At least 132 subjects will be randomized to 50, 100 or 200 mg X-
82 versus placebo in a 1:1:1:1 ratio (33:33:33:33 subjects). 
Gender/Age 
Males and females, 50 years of age or older 
Number & location of 
Centers 
35 to 45 sites in the USA 
Key Eligibility Criteria 
Males and females, aged 50 years or older with wet AMD 
diagnosed for at least 6 months and receiving ivt anti-VEGF at 
least every 8 weeks for the past two injections and have 
demonstrated a reduction in macular fluid or macular thickness 
compared to the OCT prior to the last anti-VEGF injection at Day 
-29. BCVA must be 20/320 (25 letters) or better in both eyes. 
Subjects may not have undergone any intraocular surgery of the 
study eye within 6 months of screening. Previous posterior 
vitrectomy of the study eye is not allowed within 30 days of 
Screening Visit 1 
Investigational Product 
Multiples of 50 mg and 100 mg X-82 tablets or matching placebo 
tablets administered per os (po) once a day (qd). 
Study Procedures 
Subjects will be screened for inclusion into the study after 
providing written informed consent between Day -29 and Day -1. 
Screening procedures to be performed between Day -14 and Day 
-1 
will 
include 
ECG, 
laboratory 
analyses, 
BCVA, 
ophthalmological examination, IOP, FA, fundus photography and 
SD-OCT and subjects will need to demonstrate a reduction in 
macular fluid or macular thickness after receiving an injection of 
anti-VEGF at Day -29. On Day -1 (28 days after the initial anti-
VEGF injection) subjects will receive a further injection of anti-
VEGF and then be dispensed with study medication to be 
commenced the following day, and which will be taken with food 
at the same time each day for the duration of the study. Subjects 
will return for study assessments every 4 weeks until week 52. 
Follow-up assessments will occur at week 56. Subjects will be 
assessed for the need for retreatment with anti-VEGF therapy 
based on specific retreatment criteria. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Clinical Parameters 
The following clinical parameters will be evaluated: 
Slit lamp examination 
Fundus examination  
Intraocular pressure  
Best corrected visual acuity (ETDRS) 
Fluorescein angiography/fundus photography 
Spectral Domain Optical coherence tomography  
Safety Assessments 
Systemic and ocular safety will be evaluated by assessing:  
ECG 
Laboratory analyses 
Adverse events (AEs) 
Serious adverse events (SAEs) 
Efficacy Outcomes 
Primary efficacy measure: 
The mean change in ETDRS visual acuity score at week 52 
Secondary efficacy measures:  
The mean number of anti-VEGF injections at week 52  
Change in OCT parameters from Day -1 to week 52 
Change in FA parameters from Day -1 to week 52 
Time from Day 1 to first anti-VEGF injection 
 
Interim analyses 
One interim analysis will be performed to enable the DSMB of 
the trial to perform a full benefit/risk assessment and recommend 
a course of action to Sponsor. A second interim analysis will be 
performed to enable the DSMB and a small group of individuals 
designated by the Sponsor to plan future trials of X82 in wet 
AMD or other indications. 
 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
1 
INVESTIGATOR SIGNATURE PAGE 
 
 
A randomized, double-masked, placebo-controlled, dose-finding, non-inferiority study of X-82 
plus prn ivt anti-VEGF compared to prn ivt anti-VEGF monotherapy in neovascular AMD. 
 
My signature confirms that I have carefully read, and that I understand this protocol. I agree to 
follow the study procedures as outlined in this protocol in compliance with Good Clinical 
Practice and all other regulatory requirements. 
 
This protocol contains confidential information with respect to products and clinical trials. I 
agree to hold this information in confidence and not to disclose it to any third parties until this 
information becomes a matter of public knowledge, or until a formal agreement for that purpose 
has been entered into by the parties. 
 
 
_________________________________ 
Print Name of Investigator 
 
 
_________________________________ 
__________________ 
 
Date 
 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
2 
TYROGENEX SIGNATURE PAGE 
 
 
TITLE: 
A randomized, double-masked, placebo-controlled, dose-finding, 
non-inferiority study of X-82 plus prn ivt anti-VEGF compared 
to prn ivt anti-VEGF monotherapy in neovascular AMD 
 
Protocol Author:  
Daniel E. Salazar, Ph.D. 
 
Date: 
 
Signature:___________________________ 
Please see electronic signature page at the end of this document.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
TABLE OF CONTENTS 
  
PROTOCOL SUMMARY
1
INVESTIGATOR SIGNATURE PAGE
2
TYROGENEX SIGNATURE PAGE
ABBREVIATIONS
3
INTRODUCTION
3.1
AGE-RELATED MACULAR DEGENERATION (AMD)
3.2
CLINICAL PATHOLOGY
3.3
PHARMACOLOGIC TREATMENT OF NEOVASCULAR AMD
3.3.1
ANTI-VEGF THERAPY ............................................................................... 13
3.3.2
PLATELET-DERIVED GROWTH FACTOR (PDGF) ........................................ 13
3.4
X-82 - A LOW-TOXICITY VEGFR/PDGFR INHIBITOR
3.4.1 NON-CLINICAL STUDIES OF X-82 .............................................................. 14
4
STUDY OBJECTIVE
5
STUDY DESIGN
5.1
SAMPLE SIZE, AND NUMBER AND LOCATION OF SITES
6
INVESTIGATIONAL TREATMENT (X-82) AND CONCOMITANT 
MEDICATIONS
6.1
50 MG AND 100 MG X-82 AND PLACEBO TABLETS
6.2
X-82 DOSING
6.3
RE-TREATMENT WITH ANTI-VEGF
6.4
CONCOMITANT MEDICATIONS
6.4.1 PROHIBITED CONCOMITANT MEDICATIONS .............................................. 21
7
STUDY POPULATION
7.1
INCLUSION CRITERIA
7.2
EXCLUSION CRITERIA
8
PHARMACOKINETICS
8.1
PHARMACOKINETIC SAMPLING
8.2
PHARMACOKINETIC DATA ANALYSES
9
SUBJECT ENROLLMENT, TREATMENT AND SCHEDULE OF VISITS
9.1
SCREENING AND INFORMED CONSENT
9.2
DAY -29: SCREENING VISIT 1  ANTI-VEGF TREATMENT
9.3
DAY -14 (+7): SCREENING VISIT 2 - CONFIRMATION  OF RESPONSE TO 
ANTI-VEGF
9.4
DAY -1 [28 DAYS AFTER DAY -29 (+3)]: RANDOMIZATION
9.5
WEEKS 4 TO 48 (+7)


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
9.6
WEEK 52 AND EARLY TERMINATION (+7)
9.7
WEEK 56: (OR ONE MONTH POST-X82 TREATMENT) FOLLOW-UP VISIT 
(+7)
9.8
CLINICAL PARAMETERS AND DIAGNOSTIC TESTS
9.8.1
HISTORY AND VITAL SIGNS ....................................................................... 28
9.8.2
ELECTROCARDIOGRAM (ECG) ................................................................... 28
9.8.3
COMPLETE BLOOD COUNT (CBC) WITH DIFFERENTIAL ............................ 28
9.8.4
COMPREHENSIVE METABOLIC PROFILE (CMP) ......................................... 28
9.8.5
THYROID FUNCTION .................................................................................. 28
9.8.6
ADDITIONAL SERUM TESTS: LIPASE, AMYLASE AND CREATINE 
KINASE MEASUREMENT ............................................................................. 28
9.8.7
URINALYSIS ............................................................................................... 28
9.8.8
PHARMACOKINETIC (PK) SAMPLING ......................................................... 28
9.8.9
PHARMACOGENETIC (PG) SAMPLING ......................................................... 29
9.8.10 OPHTHALMIC ASSESSMENTS ............................................................ 29
9.8.11 RESTRICTION ON THE LIFESTYLE OF SUBJECTS .......................... 30
10
INVESTIGATIONAL PRODUCT
10.1
LABELING, PACKAGING, AND SUPPLY
10.2
PREPARATION AND ADMINISTRATION OF INVESTIGATIONAL PRODUCTS
10.3
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCTS
10.4
SAFETY MONITORING RULES
10.5
STOPPING RULES FOR LIVER CHEMISTRY ELEVATIONS
10.6
DOSE MODIFICATIONS FOR TOXICITY
11
STATISTICAL PLAN
11.1
EFFICACY OUTCOMES AND HYPOTHESES
11.1.1 PRIMARY EFFICACY OUTCOME .................................................................. 33
11.1.2 SECONDARY EFFICACY OUTCOME ............................................................. 33
11.1.3 OTHER EFFICACY OUTCOMES .................................................................... 34
11.2
SAFETY MEASURES
11.3
SAMPLE SIZE JUSTIFICATION
11.4
TESTING PROCEDURE
11.5
RANDOMIZATION
11.6
ANALYSIS POPULATIONS
11.7
INTERIM ANALYSES
11.7.1 INTERIM ANALYSIS 1 ................................................................................. 35
11.7.2 INTERIM ANALYSIS 2 ................................................................................. 35
11.8
STATISTICAL METHODOLOGY
11.8.1 EFFICACY ................................................................................................... 36


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
11.8.2 SAFETY ...................................................................................................... 37
12
SAFETY REPORTING
12.1
DEFINITIONS OF ADVERSE EVENTS
12.2
ADVERSE EVENT RECORDING AND REPORTING
12.2.1 CLASSIFICATION OF ADVERSE EVENTS BY INTENSITY/SEVERITY .............. 40
12.2.2 EXPECTEDNESS .......................................................................................... 40
12.2.3 RELATEDNESS ............................................................................................ 41
12.2.4 OUTCOME .................................................................................................. 41
12.2.5 TREATMENT OR ACTION TAKEN ................................................................ 41
12.3
SERIOUS ADVERSE EVENT REPORTING
12.4
UNMASKING
13
STUDY COMPLETION
13.1
SUBJECT DISCONTINUATION
13.2
LOST TO FOLLOW UP
13.3
EARLY SUBJECT TERMINATION / SUBJECT WITHDRAWAL
13.4
FOLLOW-UP OF SUBJECTS WITH ADVERSE EVENTS
13.5
STUDY SUSPENSION, TERMINATION AND COMPLETION
14
ETHICAL AND REGULATORY CONSIDERATIONS
14.1
COMPLIANCE STATEMENT, ETHICS AND REGULATORY COMPLIANCE
14.2
IRB APPROVAL
14.3
INFORMED CONSENT
14.4
SUBJECT CONFIDENTIALITY
15
RECORD KEEPING AND RETENTION
15.1
AMENDMENTS TO THE PROTOCOL
15.2
DOCUMENTATION REQUIRED TO INITIATE THE STUDY
15.3
STUDY DOCUMENTATION AND STORAGE
15.4
DATA COLLECTION
15.5
STUDY MONITORING, AUDITING, AND INSPECTING
15.6
DISCLOSURE AND PUBLICATION POLICY
16
REFERENCES
APPENDIX 1 SCHEDULE OF ASSESSMENTS
APPENDIX 2 DRUGS WITH A KNOWN RISK OF TORSADES DE POINTES 
AND/OR THAT PROLONG QT INTERVAL SHOULD BE USED WITH 
CAUTION.
APPENDIX 3  COMMON P450 INHIBITORS, INDUCERS AND SUBSTRATES
DRUG DEVELOPMENT AND DRUG INTERACTIONS:  TABLE OF 
SUBSTRATES, INHIBITORS AND INDUCERS


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 COMMITMENTS
APPENDIX 5 INVESTIGA
 AND RESPONSIBILITIES
APPENDIX 6 DECLARATION OF HELSINKI
APPENDIX 7 ASSESSMENT OF VISUAL ACUITY
APPENDIX 8: AREDS LENS GRADING PROCEDURE


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
ABBREVIATIONS 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AMD 
Age-related macular degeneration 
ANC 
Absolute neutrophil count 
AREDS 
Age-Related Eye Disease Study 
AST (SGOT) 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma-concentration time curve 
AUC0-t 
Area under the plasma-concentration time curve from zero up to the last 
measureable concentration 
AUC0-24 
Area under the plasma-concentration time curve from time zero to 24 hours   
BCVA 
Best corrected visual acuity 
BPM 
Beats per minute 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CHF 
Congestive heart failure 
C-Kit 
CD117 cytokine receptor 
Cmax 
Peak drug concentration 
CMP 
Comprehensive metabolic profile 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
CRT 
Central retinal thickness 
CSF 
Colony-stimulating factor 
CT 
Computerized tomography 
CTCAE 
DARC 
Common Terminology Criteria for Adverse Events 
Digital Angiographic Reading Center 
DLT 
Dose Limiting Toxicity 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ECHO 
Echocardiogram 
FA 
Fluorescein angiography 
FDA 
Food and Drug Administration 
GIST 
Gastrointestinal stromal tumor 
HIPAA 
Health Insurance Portability and Accountability Act 
HNSTD 
Highest non-severely toxic dose 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
ICF 
Informed Consent Form 
IB 
IRC 
 
Independent Reading Center 
INR 
International normalized ratio 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IVT 
Intravitreal 
MI 
Myocardial infarction 
MTD 
Maximum tolerated dose 
N/A 
Not applicable 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
NYHA 
New York Heart Association 
PDGF 
Platelet derived growth factor  
PDGFR 
Platelet derived growth factor receptor  
PDT 
Photodynamic therapy 
PG 
Pharmacogenetic 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PO 
Per os, orally 
PR 
Progesterone receptor 
PR+ 
Progesterone receptor positive 
PVC 
Polyvinyl chloride 
QA 
Quality assurance 
QTcF 
QT interval corrected for heart rate using the Fridericia method of correction 
RAP 
Retinal angiomatous proliferation 
RPE 
Retinal pigment epithelium 
RET 
RET onco-
 
RTK 
Receptor tyrosine kinases 
SAE 
Serious adverse event 
SD-OCT 
Spectral Domain Optical coherence tomography 
STD10 
Severely toxic dose in 10% of animals 
T1/2 
Terminal half-life 
TKI 
Tyrosine kinase inhibitor 
TTP 
Time to tumor progression 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor  
VEGFR 
Vascular endothelial growth factor  receptor 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
 
3.1 
AGE-RELATED MACULAR DEGENERATION (AMD) 
Age-related macular degeneration (AMD) is one of the most common causes of vision loss 
among adults in the United States of America (USA) and other developed countries.  Late AMD 
is 
, neovascular or wet 
form.  Although only about 10% of people with AMD will develop the neovascular form of the 
disease, neovascular AMD (nAMD) accounts for 90% of the blindness associated with AMD [1].  
In nAMD, severe vision loss is caused by abnormal blood vessels that invade the macula, the 
region providing sharp resolution and central vision.  Leakage from these vessels, as well as the 
vessels themselves, causes progressive deterioration in central vision.  In functional terms, 
people with nAMD are unable to read, recognize faces or drive, and the disease often leads to 
legal blindness.  The onset of severe visual changes in nAMD can occur suddenly.  Neovascular 
AMD progresses much more quickly than dry AMD.  Within the nAMD category, classic 
choroidal neovascularization (CNV), in the center of the fovea, is largely responsible for vision 
loss occurring in a matter of weeks.  While occult CNV may progress very slowly, 70% of 
individuals with untreated subfoveal CNV became legally blind (20/200) within nine months of 
diagnosis [2].  
There are approximately 1.75 million people in the USA with impaired vision resulting from 
AMD, a number that is expected to triple by the year 2030 as the population ages [3].   
3.2 
CLINICAL PATHOLOGY 
The clinical and histopathological features of AMD include a relationship with age, and the 
presence of pigmentary disturbances, drusen, thickening of Bruch's membrane which is the 
innermost layer of the choroid, and basal laminar deposits.  Age-related macular degeneration is 
an advanced stage of a deteriorative process that takes place in all eyes.  The primary lesion in 
AMD appears to reside in the retinal pigment epithelium (RPE), possibly resulting from its high 
rate of molecular degradation. Beginning early in life, and continuing throughout the life span, 
cells of the RPE gradually accumulate sacs of molecular debris.  These residual bodies 
(lipofuscin) are remnants of the incomplete degradation of abnormal molecules which have been 
damaged within the RPE cells or derived from phagocytosed rod and cone membranes.  
Progressive engorgement of RPE cells with these functionless residues is associated with the 
extrusion of aberrant materials which accumulate in Bruch's membrane and aggregate in the 
form of drusen and basal laminar deposits.  These excretions contribute to the further 
deterioration of the RPE.  Loss of vision results from death of visual cells due to degeneration of 
RPE cells, or the effects of leakage from neovascular membranes that invade the region of 
abnormal extracellular deposits [4].  In particular, when lesions invade the macula and the fovea 
centralis, central visual loss occurs which impairs facial recognition and the ability to read and to 
drive a vehicle. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
3.3 
PHARMACOLOGIC TREATMENT OF NEOVASCULAR AMD 
3.3.1 Anti-VEGF Therapy 
A significant proportion of subjects diagnosed with the neovascular form of AMD can be treated 
with drugs that target abnormally high levels of the specific angiogenic growth factor vascular 
endothelial growth factor (VEGF).  VEGF is up-regulated in eyes with neovascular AMD, and 
promotes the growth of abnormal blood vessels, as well as causing these to leak plasma into the 
back of the eye resulting in significantly reduced visual acuity over time.  Ranibizumab 
(Lucentis; Genentech) and bevacizumab (Avastin; Genentech) have been designed to block all 
isoforms of VEGF.  Most recently, aflibercept (Eylea; Regeneron Pharmaceuticals) was 
approved for intravitreal injection in subjects with nAMD; aflibercept binds VEGF-A and PIGF 
(placental growth factor) to inhibit the binding and activation of these VEGF receptors.  
These anti-VEGF therapies have been efficacious for many subjects, particularly in the initial 
phases of treatment, but require intravitreal injections at monthly or six-weekly intervals.  It is 
now established that a failure to main
-
initial aggressive anti-VEGF therapy, results in the reappearance of the disease pathophysiology 
within a few months after cessation of anti-VEGF therapy necessitating frequent costly 
intravitreal treatment to affected eyes.  Furthermore, these monthly intravitreal injections are 
associated with risks of endophthalmitis, retinal detachment, intraocular hemorrhage, increased 
intraocular pressure and even anaphylaxis.  Thus, there is a need for a product which can 
prevent, or, attenuate the requirement for further anti-VEGF therapy once the pathophysiology 
has been initially arrested by anti-VEGF therapy or, replace this approach with a longer lasting 
treatment.   
3.3.2 Platelet-Derived Growth Factor (PDGF) 
There is growing evidence that the pathophysiology of nAMD involves multiple growth factors 
beyond VEGF, and there is likely a clinical benefit to targeting multiple pathways 
simultaneously. 
The development and propagation of neovascularization involves pro-
angiogenic factors, vascular permeability molecules, and inflammatory proteins.  While targeting 
a specific pathophysiologic mechanism, such as VEGF, is effective in halting vascular leakage, it 
has shown to be only a temporizing treatment.  Further benefit may be realized if several 
components of the cascade are treated simultaneously [13,14]. 
Platelet-derived growth factor (PDGF) is a growth factor implicated in angiogenesis and 
formation of nAMD.  In contrast to VEGF, which acts on the endothelial cells that line 
targeting VEGF and PDGF simultaneously has been shown to be synergistic for inhibiting blood 
vessel growth in tumors [15] and in animal models of nAMD [16,17].  As such, clinical studies 
are underway with other treatment regimens that inhibit both VEGF and PDGF simultaneously 
[18,19]. 
Systemic toxicities associated with early generation VEGFR/PDGFR inhibitors have precluded 
long-term use of these agents in ophthalmology [20].  The advent of newer generation 
VEGFR/PDGFR inhibitors with improved therapeutic indices may offer a therapeutic alternative 
for neovascular AMD therapy that would enable delivery of a potent anti-angiogenic agent via 
the oral route.  


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
3.4 
X-82 - A LOW-TOXICITY VEGFR/PDGFR INHIBITOR  
X-82 is an oral multi-kinase VEGFR/ PDGFR inhibitor intended for the treatment of pathologic 
angiogenesis in diseases such as nAMD, von Hippel-Lindau disease and solid tumors. The 
growth factors VEGF and PDGF are both implicated in the pathogenesis of nAMD, and there is 
growing evidence that combined inhibition of VEGF and PDGF has a synergistic effect for 
treatment of nAMD. 
Mechanistically, binding of X-82 to its target receptors, i.e., VEGFR and PDGFR, results in 
inhibition of angiogenesis.  X-82 is structurally related to an earlier multi-kinase inhibitor 
sunitinib and has been designed to improve upon the safety profile without compromising the 
efficacy of sunitinib. In a diverse panel of human tumor nude mouse xenograft models  
X-82 displayed comparable activity to sunitinib with respect to tumor growth inhibition. Models 
of renal cell, colon, pancreatic, melanoma, and leukemia were studied. In these studies the 
minimum effective dose that gave at least 50% inhibition of tumor growth in a sensitive model 
was 40 mg/kg twice a day (BID). X-82 has also been tested in a rat model of choroidal 
neovascularization (CNV), and it was observed to inhibit CNV at both dose levels tested. 
Based on the toxicology studies, with an STD10 in the rat of 20 mg/kg (120 mg/m2) daily, 20 mg 
(capsule formulation) was selected as the starting dose for the first-in-human clinical trial of X-
82.  The initial clinical evaluation of X-82 is being conducted under IND 108,192, in subjects 
with solid tumors (Protocol X82-CLI-101). To date, 16 subjects treated at doses ranging from 20 
to 400 mg qd and 140 to 200 mg BID (capsule formulation). Subsequently a tablet formulation 
was developed and 36 subjects have been treated at doses ranging from 50 to 800 mg qd. Among 
the total of 52 subjects treated to date, X-82 has been well tolerated, with generally mild adverse 
events reported.  A maximum tolerated dose has not yet been reached in this ongoing study. 
There is an apparent saturation in absorption of the drug at doses close to 400 mg qd. The same 
tablet formulation has been evaluated in the Phase 1 protocol for AMD (Protocol X82-OPH-102) 
and will also be used in the phase 2 protocol. 
This Phase 2 clinical protocol is designed to evaluate the safety and provide preliminary 
evidence of efficacy of X-82 tablets for the treatment of choroidal neovascularization secondary 
to AMD. 
 Non-Clinical Studies of X-82
 
To assess the safety of X-82, a single escalating dose study was conducted in dogs followed by a 
seven day repeated dose phase, a 28-day dose range-finding study was conducted in rats, and  
28-day repeated dose toxicity studies in rats and dogs were conducted.  In the toxicology studies, 
X-82 was administered orally in order to mimic the planned mode of clinical administration.    
In the 28-day repeat-dose toxicity study in the rat, the STD10 was determined to be  
20 mg/kg/day, the lowest dose tested.  Effects seen at this dose included slightly reduced weight 
gain (2% to 6%), slight reduction in red cells (3% to 15%), elevated ALT and AST (20-100% 
above control; return to normal at end of recovery period), and mild adrenal vacuolation (males 
only) and adrenal hypertrophy (females only) which was designated by the pathologist as a non-
adverse finding.  Hypertrophy of the bone cartilage and growth plate was seen in females only.  


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Other changes at this dose were typical of antineoplastic agents, and included extramedullary 
hematopoiesis, hypocellularity of the bone marrow, and thymic depletion.   
At higher doses, toxicological effects were largely the same, but were increased in severity, 
particularly in the females, and many were typical for oncology agents.  In dogs, a dose of  
100 mg/kg/day (the highest dose tested) was determined to be the highest non-severely toxic 
dose (HNSTD).  Findings in this study, primarily seen at 50 and 100 mg/kg/day, included 
emesis, slightly lower weight gains, increases in red cells (males only), decreased white cell 
counts, and elevated liver enzymes.  Histopathological changes were limited to decreased 
cellularity of the bone marrow.  None of these changes were considered serious in nature, and all 
had resolved by the end of the recovery period. Yellow hair coat, a characteristic of X-82, was 
seen in both species.   
A phototoxicity study conducted in guinea pigs at 30 and 120 mg/kg found that X-82 caused 
transient erythema for up to 3 hours post exposure to ultraviolet light and is therefore, phototoxic 
in this species. 
Two further repeat dose toxicology studies were also performed in rats and dogs. The first was a 
26 week study in rats and the other was a 39 week study in dogs. 
The 26 week rat study concluded that administration of X-82 to rats for up to 182 consecutive 
days at 5, 10, or 20 mg/kg/day in males and 1, 3, or 10 mg/kg/day in females did not result in 
adverse effects at any dose level.  Following 182 days of dosing, minor X-82-related effects 
included increased body weight and body weight gain in animals at all dose levels, minimally 
decreased red blood cell count and minimally increased mean corpuscular volume and mean 
corpuscular hemoglobin in females given 10 mg/kg/day and males given 20 mg/kg/day, 
increased adrenal gland weights in females given 10 mg/kg/day, increased vacuolation in adrenal 
 mg/kg/day and females given 10 mg/kg/day, decreased 
 mg/kg/day and females given 10 mg/kg/day, 
and increa
 mg/kg/day 
and females given 10 mg/kg/day.  The no observed adverse effect level (NOAEL) is 
20 mg/kg/day for males and 10 mg/kg/day for females. 
Likewise the 39 week dog study at 12.5, 25, or 50 mg/kg/day of X-82 concluded that the only 
adverse effect was tubular degeneration/atrophy in the testes at >12.5 mg/kg/day observed at 
interim or terminal sacrifice.  Other minor, nonadverse, X-82-related effects included reduced 
intraluminal sperm in epididymis in one male at 12.5 mg/kg/day (interim sacrifice only) and 
yellow discoloration of the haircoat, minor protein concentration changes, decreased testis and 
epididymis weights, cellular debris and/or reduced intraluminal sperm in the epididymis, 
increased extramedullary hematopoiesis in the spleen, and hypocellular bone marrow for animals 
given >25 mg/kg/day.  Based on these results, the no observed adverse effect level (NOAEL) of 
X-82, when administered for at least 39 weeks, is 50 mg/kg/day for females and was not 
achieved for males. 
Additional information on the X-82 toxicology studies conducted to date is provided in the 
. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
After a single dose with a suspension formulation of X-82, the measures of exposure, Cmax and 
AUC0-t or AUC0-24 increased with increasing dose for X-82, although the increases were not 
linear at the highest dose.  X-297, the major metabolite, is rapidly produced and absorbed.  After 
7 or 28 days of repeated dosing, the values for Cmax and AUC0-24 were similar or lower than on 
Day 1.  On Day 1 in the rat study values for t1/2 ranged from 2.8 to 5.0 hr for X-82 and from 2.6 
to 8.6 hr for X-297.  For dogs on Day 1, the mean values for t1/2 ranged from 1.5 to 2.2 hr for X-
82 and from 1.5 to 3.4 hr for X-297. In a tissue distribution study in mice, the concentrations of 
X-82 were similar in the plasma and tumor following administration of the suspension 
formulation.  The concentrations in the liver and kidney were higher than the plasma 
concentration, indicating probable involvement in the metabolism and elimination of X-82.  The 
concentrations in the fat, lung, heart, and spleen were similar or slightly lower than the plasma, 
and concentrations in the muscle and brain were approximately 40% and 6% of the plasma 
concentrations. 
The plasma protein binding of X-82 was determined in vitro.  There was no apparent dependence 
of % free drug on concentration in any of the species evaluated. In rats, the % free X-82 was 
approximately 0.3%.  For mice, the % free X-82 was approximately 1.5%.  For dogs, monkeys, 
and humans, the % free X-82 was approximately 2%.  These results indicate high protein 
binding. 
The metabolism of X-82 was studied in vitro using liver microsomes from dogs, monkeys and 
humans.  The rates of metabolism were similar for dog and human microsomes, and the rate of 
metabolism was substantially faster for monkey microsomes.  LC/MS/MS analysis revealed a 
total of 26 metabolites.  There were no human-specific metabolites; however, neither dog nor 
monkey microsomes produced all 20 of the metabolites observed with human microsomes.  
Qualitatively, the major metabolites were C17, formed by hydroxylation plus hydrogenation; 
C18, formed by dihydroxylation; and C20 (X-297), formed by N-demethylation.   
 
 
Inhibition of cytochrome P450 isozymes was assessed in vitro in pooled human liver 
microsomes by determining the effect of X-82 (10 µM) on the metabolism of the selective 
substrates phenacetin (CYP1A2), bufurarol (CYP2D6), diclofenac (2C9), (S)-mephenytoin 
(2C19), and midazolam (CYP3A4).  The results suggest that X-82 has minimal potential to 
inhibit 3A4, 2D6, 2C19 or 1A2. However, approximately 55% inhibition of CYP2C9 activity 
was observed at 10 µM of X-82, which is >5 times the mean Cmax (1.9 µM) of subjects at the 
saturation doses of 400  800 mg qd. X-82 is primarily metabolized by CYP3A4 and thus its 
concurrent use with potent CYP3A4 inhibitors or inducers should be avoided. 
A tablet formulation of X-82 with dosage strengths of 50 mg and 100 mg was developed in order 
to improve the absorption/ exposure achieved with X-82. The tablet formulation was 
administered orally to dogs under both fed and fasted conditions and was compared with the  
100 mg capsule formulation administered under fasted conditions, since that is how the drug was 
administered in the clinic.  The 100 mg tablet under fed and fasted conditions resulted in an 
AUC0-t that was approximately 3.5 - 4.8x and 2.6 - 3.6x higher, respectively, than that observed 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
with the 100 mg capsule.  Exposures with 2 x 50 mg tablets were generally similar to those 
observed with the 100 mg tablet.   
 
In a diverse panel of human tumor nude mouse xenograft models, X-82 displayed comparable 
activity to sunitinib with respect to tumor growth inhibition.  Models of renal cell, colon, 
pancreatic, melanoma, and leukemia were studied.  In these studies the minimum effective dose 
that gave at least 50% inhibition of tumor growth in a sensitive model was 40 mg/kg BID.  The 
dose of X-82 that induced a maximum effect (complete tumor stasis or regression) in most 
xenograft models was 160 mg/kg BID. 
The exposure of X-82 as measured by AUC in vivo in nude mice at the maximally effective dose 
was 67,688 ng.hr/ml.  In female rats an STD10 was observed at an AUC of 160,418 ng.hr/ml.  
Thus, there was little evidence of toxicity in rats at exposures 2.4 times the maximum efficacious 
exposure in mice.  At the minimum effective dose of X-82 in a relevant renal cell carcinoma 
(RCC) xenograft model 53% inhibition of tumor growth was observed at an exposure calculated 
to be 9.4 times lower than the STD10 in female rats.  These data suggest a very high safety 
window for X-82 that, if translatable to human, could result in maximum biologic activity with 
reduced toxicity. 
The effects of X-82 on the development of proliferative diabetic retinopathy (PDR) was 
investigated in a murine model in which oxygen is used to induce angiogenesis and subsequent 
ischemic retinopathy. X-82 was able to reduce the angiogenic response by 71.1% compared to 
controls in this model.  Furthermore, the measurement of X-82 concentrations also showed that 
the plasma and retina concentrations of X-82 were similar and thus X-82 can reach the retina via 
the leaky blood vessels seen in this model of PDR. 
 
X-82 is currently being evaluated in a Phase 1 dose-escalation study designed to evaluate safety, 
tolerability, and pharmacokinetics in subjects with advanced solid tumors, under IND 108,192 
sponsored by Tyrogenex.  In the 52 study subjects enrolled at the time the current protocol was 
prepared, generally mild adverse events have been reported.  The most frequently reported 
adverse events have been fatigue, nausea, vomiting, diarrhea, and hypertension.   A maximum 
tolerated dose (MTD) has not been reached in this ongoing study.   
Early data from this study suggest activity of X-82 in this study population, with some response 
to treatment.   
Preliminary PK data show that the half-life of X-82 in humans is <9 hours at oral doses up to 800 
mg per day. In general, there is no significant accumulation or induction after 21 days of daily 
dosing as the exposure curves on Days 1 and 22 are generally similar.  Between 50 mg and 400 
mg qd with the tablet formulation, the exposure increased with dose.  But from 400 mg to 800 
mg qd, there was little increase in exposure, suggesting absorption saturation occurs at doses  
close to 400 mg qd. The mean Cmax and AUC0-24h observed in subjects at doses of 400  800 mg 
qd are 852 ng/ml and 8609 ng.hr/ml, respectively. However, doses greater than 100 mg once a 
day result in 12-hour plasma levels >100ng/ml, the minimum exposure required for efficacy in 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
the pre-clinical anti-angiogenesis model. At 100 mg qd, the mean Cmax and AUC0-24h are 315 
ng/ml and 3130 ng.hr/ml, respectively. 
 
Twenty-nine previously treated subjects and 6 treatment naive subjects with wet AMD were 
enrolled under IND 116,264, Sponsored by Tyrogenex, Inc.  These subjects received X-82 for up 
to 6 months at the following doses: 50 mg qod (3 subjects), 50 mg qd (8 subjects), 100 mg qod (4 
subjects), 100 mg qd (10 subjects), 200 mg qd (7 subjects) and 300 mg qd (3 subjects). Subjects 
were seen every 4 weeks and underwent ETDRS VA measurement and SD-OCT for assessment 
on the need for Lucentis rescue therapy at each visit. SD-OCT images were read by the Digital 
Angiographic Reading Center (DARC), which acted as the independent reading center (IRC). 
All 35 patients maintained or improved on their baseline visual acuity scores. Of these, 25 
subjects completed the full 24 week treatment period and 15 (60%) of these subjects did not 
require any rescue therapy with Lucentis during the entire treatment period. Eight subjects (1 
who received 100 mg, 5 who received 200 mg and 2 who received 300 mg) experienced 
significant reductions in fluid on SD-OCT within the first weeks of starting X-82 and these 
observations were confirmed by the IRC. Four subjects experienced transaminase elevations, one 
of which normalized while on treatment and the remaining three returned to normal when X-82 
was discontinued. There was no dose relationship to these cases (1 case at 50 mg daily, 1 at 100 
mg every other day, 1 at 100 mg daily and 1 at 200 mg) and none were associated with any other 
laboratory abnormality or clinical symptoms. Two patients on the 300 mg doses discontinued 
treatment due to gastrointestinal symptoms - one case of mild nausea and anorexia and one of a 
grade 2 diarrhea. 
 
A recently completed study, X82-OPH-PK01, examined the urinary excretion of X-82 and its 
metabolite X-297 in healthy elderly subjects during administration of 100mg, 200 mg and 400 
mg X-82 QD per os.  The effects of renal function on total apparent clearance and renal 
clearance of X-82 and X-297 were also assessed.  The study found that the cumulative amount of 
X-82 and X-297 excreted in the urine was much less than 1% and less than 2% of the 200 mg 
oral dose (highest phase 2 dose) of X-82, respectively.  These results suggest renal elimination is 
not a major pathway for clearance of X-82 or its metabolite X-297.  Measures of plasma 
exposure to X-82 and its metabolite, X-297 (i.e., maximum plasma concentrations and AUC) did 
not increase with decreasing renal function as assessed by creatinine clearance or eGFR. There 
also was no discernible relationship between creatinine clearance or eGFR and apparent oral 
clearance (CL/F) of X-82.  There did not appear to be any discernible relationship between CLcr 
and the renal clearance of X-82 or X-297.  Nor did there appear to be any relationship between 
renal clearance of X-82 and X-297 and age in healthy subjects ranging in age from 50 to 81 years 
of age. Thus, there is little evidence that renal function will influence the pharmacokinetics of X-
82 or its metabolite, X-297. 
 
The stability of visual acuity, accompanied by changes in the SD-OCT images (fluid reductions) 
and relative infrequency of rescue therapy described in the phase 1 study above, suggests that 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
further investigation of the potential efficacy of oral X-82 in the treatment of wet AMD is 
warranted. The phase 1 study data support the conduct of a further randomized controlled 
clinical trial in subjects with previously treated nAMD.  At least 132 subjects with neovascular 
AMD will participate in this comparative study.  X-82 tablets (or matching placebo tablets) will 
be administered orally at doses of 50 mg qd, 100 mg qd and 200 mg qd.   
 
The objective of this study is to evaluate the efficacy and safety of X-82 at three doses, in 
subjects with wet AMD as determined by a comparison of the mean ETDRS visual acuity scores 
at Week 52.  
 
This is a randomized, double-masked, placebo-controlled study in which at least 132 subjects 
will be randomized to receive either 50 mg, 100 mg or 200 mg of X-82, or matching placebo 
tablets daily for 52 weeks. Subjects requiring frequent injections of ivt anti-VEGF (an interval no 
greater than 8 weeks) and with the presence of any macular fluid and macular thickness on SD-
OCT will receive a further injection of anti-VEGF during Screening Visit 1 and return for 
Screening Visit 2 to document a reduction in macular fluid or macular thickness, which will be 
confirmed by the Independent Reading Center (IRC). If a subject does not demonstrate any 
reduction of macular fluid or macular thickness at Screening Visit 2 and the investigator believes 
the subject may not have had enough time to achieve a reduction, subjects may be re-screened 
for Screening Visit 2 as long as the visit occurs within the protocol specified window [Day -14 
(+/- 7 days)]. Subjects with a reduction in macular fluid or macular thickness will undergo 
additional screening assessments and be enrolled in to the study.   Subjects will receive a further 
injection of anti-VEGF at Day -1 and start study treatment the following day. All subjects will 
remain on study treatment for 52 weeks and be assessed for the need for further injections of 
anti-VEGF every 4 weeks for that period.  
5.1 
SAMPLE SIZE, AND NUMBER AND LOCATION OF SITES 
At least one hundred and thirty two (132) subjects will be randomized to either 50, 100 or 200 
mg X-82 versus placebo qd in a 1:1:1:1 ratio (33:33:33:33 subjects) at 35 to 45 sites in the US. 
As much as a 20% rate of early discontinuation is accounted for in the power calculations. (See 
Section 11.3). 
 
6.1 
50 MG AND 100 MG X-82 AND PLACEBO TABLETS 
X-82 (50 mg and 100 mg doses) and matching placebo are formulated as identical round orange 
tablets and are provided in a 60 cc round high density polyethylene (HDPE) bottle containing 30 
tablets, a desiccant canister and sealed with a white PP child-resistant (CR) cap with a heat-
induction sealed inner liner. 
The tablets should be stored at room temperature (15°C-30°/59°F-86°F). 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
6.2 
X-82 DOSING  
In this clinical trial, X-82 or matching placebo, will be administered per os (po) at a dose of 50 
mg, 100 mg, or 200 mg, or matching placebo tablets qd. Subjects will be instructed to take one 
tablet from each of the two bottles provided. Subjects randomized to placebo will be dispensed 
with two bottles of placebo; subjects assigned to 50 mg will receive one bottle of 50 mg tablets 
and one bottle of placebo tablets: subjects assigned to 100 mg will receive two bottles of 50 mg 
tablets; subjects assigned to 200 mg will receive two bottles of 100 mg tablets. 
The tablets should be taken with food, preferably at the same time each day. The subjects should 
note if the study medication was taken with a meal. No alcoholic beverages may be consumed 
during the 2 hours prior to taking their study medication and subjects must abstain from 
consuming any alcoholic beverages for a minimum of 2 hours after taking their study 
medication. Subjects should confirm at each visit that the study medication was not consumed 
within 2 hours of consuming a beverage containing alcohol.  
The time of day for administration of study tablets should be consistent for each subject. If the 
subject misses a dose of study medication, the subject should take the dose as soon as possible, 
but not less than 12 hours before the next dose is scheduled for administration. If the next dose is 
scheduled for less than 12 hours, the subject should skip the missed dose and take the next dose 
as scheduled.  Subjects will keep a dosing diary for the duration of the study and this should be 
reviewed with the subjects at each visit. X-82 is 1000 times more soluble in ethanol than in 
aqueous buffers and therefore the consumption of X-82 with alcohol could increase the systemic 
absorption of X-82 by increasing its solubility in the GI tract. 
6.3 
RE-TREATMENT WITH ANTI-VEGF 
In addition to the experimental drug, X-82 or matching placebo, subjects will be assessed on the 
need for injections of ivt anti-VEGF. Injections may be Avastin, Lucentis or Eylea, but should 
remain the same treatment as the subjects were receiving at the time of enrollment into this study 
and should be based on the following criteria: 
Any increase in macular fluid or macular thickness (or the presence of any fluid if 
the Screening Visit 2 scan was completely dry)  compared to the SD-OCT scan 
observed at Screening Visit 2.  This includes visible subretinal fluid, visible 
intraretinal cysts, or an increase in size or new PED (documented by SD-OCT 
images).  
or 
New or increased macular hemorrhage (documented by fundus photographs) 
 
Any vision loss, which is not accompanied by the presence of fluid or hemorrhage, should be 
investigated (by FA or other means) to determine the cause. 
 
Images will be transmitted to the reading center for review. 
6.4 
CONCOMITANT MEDICATIONS 
All concomitant medications taken by the study subjects within 7 days prior to the first dose of 
study drug will be documented at baseline.  Additionally, at each visit, the investigator will ask 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
the subject about any new medications he/she is taking or has taken after the start of the study 
drug and this information will also be documented in the study case report forms. 
 
The wash out period for non-herbal medications is 29 days (starting at Screening Visit 1) and 7 
days for herbal medications.  The following non-study treatments are prohibited during study 
participation from Day -29 (and Day -7 for herbal medications):  
 Radiation therapy, hormonal therapy for cancer (with the exception of LHRH agonists for 
prostate cancer), cancer chemotherapy, cancer immunotherapy or other biologic therapy. 
 Other investigational drugs within thirty (30) days or 5 half-lives, whichever is longer, of 
Day -1.  
 Chronic treatment (> 7 days) with systemic steroids (dose >10 mg daily or 20 mg every 
other day of prednisolone or equivalent) or other immunosuppressive agents.  Topical or 
inhaled corticosteroids are allowed. 
 
Concomitant treatment with any medication which may cause QT prolongation or torsade 
de pointes should be used with caution. A list of these medications is provided in 
Appendix 2. 
 Common inhibitors, inducers and substrates of P450, including CYP3A and potent 
CYP3A4 inhibitors or inducers (see Appendix 3 for full list of such drugs). 
 
 is not permitted throughout the trial. Subjects should discontinue use at 
least 7 days prior to the first dose of study drug. 
 
 Warfarin and other coumarin anticoagulants (e.g. acenocoumarol, phenprocoumon, 
fluindione) are not permitted throughout the trial.  If treatment with a coumarin 
anticoagulant is initiated during the trial, X-82 must be discontinued immediately.  
 
7.1 
INCLUSION CRITERIA 
Subjects must meet the following criteria: 
1. Participants must have neovascular AMD (Fluid must be present at Day -29 and the IRC 
must confirm eligibility of SD-OCT images prior to randomization) which has been 
diagnosed and treated with anti-VEGF in one or both eyes for at least 6 months prior to 
joining the study and has required at least two prior injections of ivt anti-VEGF at 
intervals of not greater than 8 weeks (+ 7 days) for the past two injections in the eye that 
is selected to be the study eye (the injection to be administered on Day -29 will be, at 
minimum, the third such injection and these final three injections must be with the same 
ivt anti-VEGF therapy). 
2. Must have demonstrated the ability to achieve a reduction in macular fluid or macular 
thickness in the study eye at Screening Visit 2 (Day -14) following an injection of ivt 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
anti-VEGF at Screening Visit 1. (General thickening of the retina without visible cystic 
changes or subretinal fluid is not exclusionary for the study at Screening Visit 2.) 
3. Early Treatment Diabetic Retinopathy (ETDRS) Best Corrected Visual Acuity (BCVA) 
of 25 letters (20/320) or better in both eyes. 
4. 
. 
5. Adequate bone marrow function: 
a) Absolute neutrophil 
2500 cells/mm3; 
130,000 cells/mm3; 
10.0 g/dL; 
6. Adequate hepatic function: 
a) Total bilirubin within the institutional ULN (Subjects with an increased total bilirubin 
secondary to a geneticall
 may be considered 
for inclusion after discussion with the medical monitor); 
2 times the institutional ULN 
7. Adequate renal function; calculated GFR of > 30 mL/min/1.73 m2  (CKD-EPI 
calculation). 
8. TSH and free T4 within normal limits (unless approved by Study Medical Monitor). 
9. Ability to swallow and retain oral medication. 
10. Willing and able to provide written informed consent, comply with the investigational 
study protocol and return for all study visits and continue to receive the same anti-VEGF 
therapy they received at Screening Visit 1 on an as needed basis.  
7.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following criteria will be excluded from study participation: 
1. Vitrectomy to the study eye within 30 days of Screening Visit 1. 
 
2. CNV due to causes other than AMD, including ocular histoplasmosis syndrome, angioid 
streaks, multifocal choroiditis, choroidal rupture, or pathologic myopia (spherical 
-8 diopters).  
 
3. Proliferative diabetic retinopathy in either eye. 
 
4. In the opinion of the investigator, any significant disease in the study eye that could 
compromise best-corrected visual acuity, e.g., glaucoma with documented visual field 
loss, severe uncontrolled glaucoma, clinically significant diabetic macular edema, 
proliferative diabetic retinopathy, ischemic optic neuropathy, uveitis, retinal 
vasculopathies including retinal vein occlusion, retinitis pigmentosa, etc. 
 
5. Trabeculectomy or aqueous shunt or valve in the study eye. 
 
6. Intraocular surgery in the study eye within three months of Day -1. 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
7. Inadequate pupillary dilation or significant media opacities in the study eye, which may 
interfere with visual acuity measurement or evaluation of the posterior segment, 
including fundus photography. 
 
8. Use of any investigational agent or participation in any other clinical trial of an 
investigational agent or investigational therapy within thirty (30) days or 5 half-lives, 
whichever is longer, of Day -1. 
 
9. Females of child bearing potential that are pregnant or not using medically acceptable 
contraception; males unwilling to take adequate contraceptive measures.  Females that 
are breastfeeding are also excluded (see Section 9.8.11 for details on contraception 
requirements).   
 
10. Serious allergy to or prior significant adverse reaction to fluorescein. Note that subjects 
that have experienced nausea or itching from the fluorescein that was treatable with 
diphenhydramine or anti-emetics that are not prohibited as concomitant medications for 
this study are not excluded.  
 
11. Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 
months prior to Screening Visit 1. 
 
12. History of myocardial infarction, ventricular arrhythmia, stable/unstable angina, 
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or 
stenting, or other significant cardiac disease within 12 months prior to Screening Visit 1. 
 
13. Any history of arterial or venous thrombosis/thromboembolic event, including pulmonary 
embolism, within the 12 months prior to Screening Visit 1. 
 
14. Any episode of atrial fibrillation in the 12 months prior to Screening Visit 1. 
 
15. Uncontrolled hypertension (BP > 160/100, despite pharmacological intervention). 
 
16. 
50 msec 
 or subjects with a history of risk 
factors for Torsades de Pointes (e.g. familial long QT syndrome, left ventricular 
hypertrophy, slow heart rate [<45 bpm] or other clinically significant abnormalities, as 
determined by the investigator. 
 
17. Current treatment with warfarin or other coumarin anticoagulants. 
 
18. Use of any drugs excluded in Section 6.4.1 (Prohibited concomitant medications and 
shown in Appendix 3. 
 
19. Any surgical procedure requiring an in-hospital stay within 28 days of Screening Visit 1. 
 
20. Invasive dental surgery within 28 days of Day-1; any planned invasive dental surgery 
during study participation. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
21. Presence of active gastrointestinal (GI) disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of X-82. 
 
22. Serious active infection, other serious medical condition, laboratory abnormality or any 
other condition that would impair the ability of the subject to administer the 
investigational drug or to adhere to the study protocol requirements. 
 
23. Presence of any condition which, in the judgment of the investigator, would prevent the 
subject from completing the study. 
 
24. Prior exposure to X-82. 
 
25. History of allergy or intolerance to Eylea, Lucentis or Avastin, or intolerance to the 
excipients in X-82 or Eylea, Lucentis or Avastin. 
 
8.1 
PHARMACOKINETIC SAMPLING 
Pharmacokinetic sampling will be performed in subjects who agree to participate to the three 
extended visits from all dose groups. Blood samples for pK analysis will be obtained on three 
separate occasions at the Week 4 Visit, Week 16 or Week 20 Visit, and Week 40 or Week 44, or 
Week 48 Visit. At each of these visits, the blood collection is to take place prior to the 
administration of X-82 (0 hr), then again at 4 hrs and finally again at between 6 and 8 hours post 
X-82 dose. The Visit number, date and times of the blood draws and date and time of X-82 
dosing are to be recorded in the source documents. 
Subjects must fast from food for at least 3 hours prior to blood draw.  Subjects are permitted to 
take prescription medications on the morning of the PK visit, but must not take their study drug 
dose until after their first blood draw (0 hr). These extended pK sampling visits are not 
mandatory, but it is hoped at least half of all participating patients will agree to them. 
8.2 
PHARMACOKINETIC DATA ANALYSES 
X-82 plasma pharmacokinetic parameters will be derived from X-82 plasma concentration-time 
data for each dose group using noncompartmental methods. 
 
9.1 
SCREENING AND INFORMED CONSENT 
potential participant.  The subject's willingness and ability to meet the follow-up requirements 
will be determined and written informed consent will be obtained.  The consenting process is to 
be documented in the source documents.  The subject will sign and date the informed consent 
form, and the investigator or his/her representative will also sign and date the consent form.  The 
original informed consent form will be retained with the subject records; a copy will be provided 
to the subject.    


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Written informed consent must be obtained before any protocol specific procedures are 
performed.  The subjects will be consented prior to the first anti-VEGF injection at day -29 
(Screening Visit 1) and some subjects may be consented prior to any prescreening period if the 
ing them in this study. 
This protocol requires that subjects demonstrate a reduction in macular fluid or macular 
thickness after receiving this first anti-VEGF injection and only after the demonstration of a 
reduction in macular fluid or macular thickness on SD-OCT (which must be confirmed by the 
reading center) can the subject be enrolled into the study after completion of the Screening Visit 
2 procedures. However, because some of the laboratory analyses take more than a week for the 
results to become available, the subjects having an OCT for confirmation of a reduction in 
macular fluid or macular thickness later than Day -14, should still have their visit 2 blood 
draw and ECGs performed no later than Day -14. 
Screening will include ECG, laboratory analyses, vital signs, pregnancy test for women of 
childbearing potential, (these assessments may be performed at either screening visit, but the 
schedule presented below is preferred) visual acuity, IOP, slit lamp and funduscopic 
examinations and must be performed prior to the second anti-VEGF injection which will occur 
on Day -1.  
9.2 
DAY -29: SCREENING VISIT 1  ANTI-VEGF TREATMENT  
After providing informed consent (if not already provided earlier for subjects being prescreened), 
and confirming the subject requires an anti-VEGF injection due to the presence of any subretinal, 
intraretinal, or sub-RPE fluid on SD-OCT, the following assessments should be completed: 
 Demographics 
 Eligibility criteria 
 Medical History 
 Ophthalmic History 
 Concomitant medications and prior AMD treatments review 
If the subject fulfills these criteria, they will receive an anti-VEGF injection and they will be 
asked to return 14 days (+/- 7 days)  later to have a further SD-OCT image taken to 
demonstrate a response to ivt anti-VEGF within 14 days (+/- 7 days) of receiving an 
injection.  
9.3 
DAY -14 (+7): SCREENING VISIT 2 - CONFIRMATION  OF RESPONSE TO ANTI-VEGF 
Subjects who demonstrate a reduction in macular fluid or macular thickness at Screening Visit 2 
will then complete the remaining screening procedures to confirm they meet the remainder of the 
study eligibility criteria and if so, be scheduled to return for another anti-VEGF injection on Day 
-1 of the protocol. Reduction in macular fluid or macular thickness will be documented in SD-
OCT images from Screening Visit 2 as compared to SD-OCT images from Screening Visit 1. 
Images will be transmitted to the reading center for further review. 
The minus 7 day window is permitted for subjects who are considered likely to demonstrate a 
reduction in macular fluid or macular thickness earlier than 14 days post-injection and the plus 7 
day window for subjects who were not able to demonstrate a reduction in macular fluid or 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
macular thickness at Day -14. The window is particularly for subjects for whom this is second 
screening attempt who had fluid at Day -14 on the previous attempt. If a re-screen visit is 
scheduled, labs and ECG should still be performed at the first visit to ensure that the results will 
be available for enrollment on Day -1.  
ALL OPHTHALMIC PARAMETERS WILL BE FOR BOTH EYES THROUGHOUT 
THE STUDY. 
 Best corrected visual acuity using ETDRS (VA) at 4 meters performed prior to dilating 
eyes (VA)  
 Spectral Domain Optical coherence tomography (SD-OCT) 
 If the Investigator 
determines there is a reduction in macular fluid or macular thickness, continue with 
Screening procedures.  If the Investigator decides to schedule a re-screen visit, labs and 
ECG should be performed, otherwise this subject will be deemed a screen failure. 
 Height, weight, BP, and pulse will be recorded. 
 ECG 
 Laboratory Assessments (see Section 9.8.3 to 9.8.6) 
 Urinalysis (and pregnancy test if appropriate - see Section 9.8.7 
 Ophthalmic examination including slit lamp and funduscopy (Ophthalmic Exam)  
 Intraocular pressure (IOP) 
 Fluorescein angiography (FA) 
 Color Fundus Photographs (Photos) 
 Record adverse events 
 Record concomitant medications 
 
9.4 
DAY -1 [28 DAYS AFTER DAY -29 (+3)]: RANDOMIZATION 
Eligible subjects who demonstrate a reduction of macular fluid or macular thickness at Screening 
Visit 2 and met all study criteria will return on Day -1 to be randomized to study treatment and 
receive a further injection of anti-VEGF. Subjects will receive their assigned study medication 
and dosing compliance log and be told to commence taking the medication the following day 
with food (Day 1) and to document the dose on the compliance log every day.   
 Mandatory ivt anti-VEGF injection 
 VA 
 Ophthalmic exam 
 IOP 
 SD-OCT 
 Subject dispensed study medication and dosing compliance log 
 Record adverse events 
 Record concomitant medications 
9.5 
WEEKS 4 TO 48 (+7) 
Participants will return every 4 weeks for the following assessments on both eyes:  
 VA 
 Ophthalmic exam 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 Vital Signs 
 IOP 
 SD-OCT 
 Laboratory Assessments and Urinalysis 
 Pharmacokinetic (pK) Sampling to occur at 3 timepoints: 
Week 4 and Week 16 or 20 and Week 40, or 44, or 48) 
 Assess the need for reinjection with ivt anti-VEGF 
 Review dosing compliance log from the previous month 
 Subject dispensed study medication and new dosing compliance log 
 Record adverse events 
 Record concomitant medications 
 ECG (Weeks 4, 12, 20, 28, 36, and 44) 
9.6 
WEEK 52 AND EARLY TERMINATION (+7) 
Participants will return at week 52 for the following assessments on both eyes:  
 VA 
 Ophthalmic exam 
 Weight and Vital Signs 
 IOP 
 SD-OCT 
 FA and Photos 
 Laboratory Assessments and Urinalysis 
 PG Sampling 
 ECG 
 Review dosing compliance log from the previous month 
 Assess the need for reinjection with ivt anti-VEGF 
 Record adverse events 
 Record concomitant medications 
9.7 
WEEK 56: (OR ONE MONTH POST-X82 TREATMENT) FOLLOW-UP VISIT (+7) 
Participants will return 4 weeks after completing treatment with study drug for the following 
assessments on both eyes:  
 VA 
 Ophthalmic exam 
 Vital Signs 
 IOP 
 SD-OCT 
 Laboratory Assessments and Urinalysis 
 Assess the need for anti-
 
 Record adverse events 
 Record concomitant medications 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
9.8 
CLINICAL PARAMETERS AND DIAGNOSTIC TESTS   
9.8.1 History and Vital Signs 
A medical history, height and weight will be recorded at Screening. Weight will be repeated 
again at Week 52. Vital signs (blood pressure and pulse) will be recorded at Screening and every 
study visit from Week 4 onwards.   
9.8.2 Electrocardiogram (ECG) 
At Screening, Week 4, 12, 20, 28, 36, and 44 and Week 52, each subject will undergo a 12-lead 
electrocardiogram (ECG).  
9.8.3 Complete Blood Count (CBC) with Differential 
CBC plus differential panel that includes white blood cells, differential, hematocrit, hemoglobin 
and platelets will be performed at Screening, and every study visit from Week 4 onwards. 
9.8.4 Comprehensive Metabolic Profile (CMP) 
A CMP that includes blood glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
magnesium, chloride, calcium, phosphate, carbon dioxide (CO2), alkaline phosphatase, AST 
(SGOT), ALT (SGPT), total bilirubin, total protein and albumin will be performed at Screening 
and every study visit from Week 4 onwards. 
9.8.5 Thyroid Function 
Serum TSH, total T3 and free T4 levels will be determined at Screening and then Weeks 4, 12, 
28 and 52. 
9.8.6 Additional Serum Tests: Lipase, Amylase and Creatine Kinase Measurement 
Serum tests for lipase, amylase and creatine kinase will be determined at the Screening and every 
study visit from Week 4 onwards. 
9.8.7 Urinalysis 
A urine dipstick will be performed at Screening and every study visit from Week 4 onwards. If 
abnormalities are present on urine dipstick, additional testing (e.g., microscopic examination, 
urinary protein: creatinine ratio, etc.) should be done as clinically indicated.  Urine pregnancy 
test will be performed at Screening Visit 2, Day -1 and every study visit for women of 
childbearing potential. If the pregnancy test is positive, the subject will be screen failed or 
discontinued from the study. 
9.8.8 Pharmacokinetic (PK) Sampling 
If subjects consent to participate in pK sampling, blood samples for pK analyses will be obtained 
on the three separate visits: 1) Week 4 Visit.  2) Week 16 or Week 20 Visit, and 3) Week 40 or 
Week 44 or Week 48 Visit.  At each of these visits, the blood samples are to be drawn at three 
different time points: 1) Prior to the administration of X-82 [0 hour and then followed by 
breakfast], 2) 4 hours post X-82 dose, and 3) 6-8 hours post X-82 dose. The acceptable window 
is +/- 30 minutes for the 4-hour time point.  The acceptable window for the 6 to 8 hour sample is 
5.5 to 8.5 hours. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
9.8.9 Pharmacogenetic (PG) Sampling 
If subjects consent to participate in PG sampling, blood will be drawn to obtain germline DNA 
samples at the Week 52 or Early Termination Visit for possible PG analyses in the event that 
outliers with respect to efficacy, tolerability/safety or exposure are identified.  
9.8.10  
OPHTHALMIC ASSESSMENTS 
9.8.10.1 Best Corrected Visual Acuity 
Manifest refraction and VA measurement must be performed according to the standard 
procedure originally developed for ETDRS and adapted for the Age Related Eye Disease Study 
(AREDS) protocol. VA testing by ETDRS protocol is detailed in Appendix 7. VA will be tested 
by trial certified examiners on both eyes, in trial certified examination rooms at every visit. 
9.8.10.2 Intraocular Pressure (IOP) 
IOP will be measured using applanation or tonopen on both eyes at every visit from Screening 
Visit 2 onward. 
9.8.10.3 Slit Lamp Examination and Funduscopy 
A slit lamp examination and funduscopy will be performed on both eyes at every visit from 
Screening Visit 2 onward. 
9.8.10.4 Spectral Domain Optical Coherence Tomography (SD-OCT) 
Spectral domain OCT (SD-OCT) will be utilized to assess subretinal fluid, intraretinal 
thickening, and neovascular lesions on both eyes at each visit. At each 4 weekly visit the 
SD-OCT. All images will be sent to the reading center 
for masked assessment. The SD-OCT machine and technician will be certified by the 
Independent Reading Center (IRC) prior to study commencement. 
The SD-OCT taken at Screening Visit 2 must be sent to the IRC for confirmation of eligibility 
within 24 hours of acquisition and confirmation of eligibility received prior to randomization. 
All other images should be sent to the IRC no more than 5 days after their acquisition, and in 
accordance with the protocol supplied by the IRC. 
9.8.10.5 Fluorescein Angiography (FA) and Color Fundus Photographs 
Fluorescein Angiograms (FAs) and Color Fundus Photographs (Photos) will be undertaken at 
screening and again at week 52. All FAs and Photos will be performed using digital fluorescein 
photography equipment and cameras certified by the IRC. The photographers undertaking FA 
and photos must be certified by the IRC prior to undertaking any angiograms on trial 
participants. The reading center will provide a protocol for image acquisition and transfer. This 
protocol must be strictly adhered to.  All images must be transferred to the IRC within 5 day of 
obtaining them.  
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
  
RESTRICTION ON THE LIFESTYLE OF SUBJECTS
9.8.11.1 Contraception Requirements  
All subjects of childbearing potential must refrain from sperm/egg donation, be abstinent, if this 
is the usual and permanent life-style choice of the subject, or if engaged in sexual relations of 
child-bearing potential (for themselves or their partner), they must use effective contraception 
from the time of signing the informed consent form until at least 14 weeks after their last dose of 
study treatment.  
For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche, and that does not meet one of the following conditions:  
 
 
 
omy  
 
For the purposes of the study, effective contraception is defined as follows:  
For male subjects:  
 
-up, 
or the use of condoms together with spermicidal foam/gel/film/ cream/suppository. Male subjects 
must also encourage their female partner to use effective contraception from the time of signing 
Effective contraceptive for the female partner includes: surgical sterilization (e.g., bilateral tubal 
ligation), hormonal contraception, intrauterine contraception/device, or barrier methods (female 
condom*, diaphragm, sponge, cervical cap) together with spermicidal foam/gel/film/cream/ 
suppository. Male subjects with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug.  
 
For female subjects:  
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 2 
barrier methods (a combination of male or female condom* with diaphragm, sponge, or cervical 
cap) together with spermicidal foam/gel/film/cream/suppository.  
 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either product failing  
9.8.11.2 Exposure to Sunlight  
All subjects should be advised of the potential phototoxicity of X-82 and advised to avoid direct 
contact with sunlight by covering arms and legs and wearing a hat and sunglasses while taking 
the study medication. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
10 INVESTIGATIONAL PRODUCT 
X-82 will be administered orally as 50 mg and 100 mg tablets to provide either a 50 mg, 100mg 
or 200 mg dose.   
Additional information can be found in the X-
 
10.1 LABELING, PACKAGING, AND SUPPLY 
X-82 Tablets (50 mg and 100 mg) are provided to the sites in HDPE Bottles with one Sorbit ½ 
Gram Desiccant Canister.  Thirty (30) tablets are included in each bottle.  Each bottle is capped 
with a Child Resistant Closure with White Liner. 
X-82 should be stored at room temperature (15ºC-30ºC/59ºF- 86ºF). 
The following information will be pre-printed on the bottle label:  Contents of the bottle, storage 
conditions, and lot number.  The label will also contain a statement to conform with FDA 
Investigational New Drug (IND) requirements as follows:  
- Limited by Federal (US) law to 
 
All trial drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for X-82 are included in the X-
 
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
10.2 PREPARATION AND ADMINISTRATION OF INVESTIGATIONAL PRODUCTS 
X-82 will be self-administered by the subject.  The investigator will instruct the subject to take 
the study drug exactly as specified in the protocol. 
10.3 ACCOUNTABILITY OF INVESTIGATIONAL PRODUCTS 
The PI (or designee) is responsible for accountability of all used and unused trial drug supplies at 
the site. 
The Sponsor or designee will verify receipt of investigational product at the site during 
monitoring visit(s), and will conduct an inventory of remaining clinical trial supplies at the site 
close-out visit.  All trial drug inventories must be made available for inspection by the monitor, 
Sponsor, or representatives of the aforementioned and regulatory agency inspectors upon 
request.  
Dispensation of investigational product will be recorded in the source document and Drug 
Accountability Records.   
e site
 and will 
accompany the clinical trial supplies that are returned to the Sponsor (or designee).  Clinical trial 
supplies must not be destroyed unless prior approval has been granted by the Sponsor or its 
representative. 
10.4 SAFETY MONITORING RULES  
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
For the purposes of safety monitoring, baseline is defined as the pre-dose value on Day 1 or, if 
no pre-dose Day 1 result is available it is the pre-dose test performed closest to Day 1.  
 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations.  
 
Confirmation Guidance: At any time during the study (Treatment or Post-Treatment Periods), the 
initial clinical laboratory results meeting the safety monitoring criteria presented below must be 
confirmed by performing measurements (ideally in the same laboratory that performed the initial 
measurement) on new specimens. All new specimen collections should take place as soon as 
possible (ideally within 3 days of the initial collection).  
 
Re-dosing Guidance: In general, subjects who do not meet the stopping rules based upon retest 
may continue dosing. However, the Investigator and the Medical Monitor (or appropriately 
qualified designee) should confer as to whether additional close monitoring of the subject is 
appropriate. If any of the stopping criteria described below (refer to Section 10.5) are met, the 
subject will be permanently discontinued from further treatment with Study Drug (X-82 or 
placebo), evaluated fully as outlined below and in consultation with the Sponsor Medical 
Monitor or appropriately qualified designee, and will be followed up in accordance with Section 
12 of the protocol.  
 
10.4.1 Safety Monitoring Rules for Liver Chemistry Tests  
In the event of an ALT or AST measurement that is > 3 x ULN or > 2 x Baseline value, 
whichever is greater, at any time during the study (Treatment or Post-Treatment Period), the 
initial measurement(s) should be confirmed as described above in Section 10.4. Similarly, 
confirmatory measurements should also be performed if ALT or AST levels increase to 5 x ULN 
(following the initial meeting of each of those criteria). If confirmed, the Investigator and 
Medical Monitor will determine the frequency of monitoring and action to be taken with Study 
Drug.  
 
Further Investigation into Liver Chemistry Elevations: For patients with confirmed ALT or AST 
levels > 3 x ULN or > 2 x Baseline value, whichever is greater, the following evaluations should 
be performed:  
 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases  
 
2. Obtain further history for concomitant drug use (including nonprescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets  
 
3. Obtain a history for exposure to environmental chemical agents and travel  
 
4. Serology for viral hepatitis sources other than HBV (HAV IgM, HCV antibody, CMV 
IgM, and EBV antibody panel)  


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA])  
 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
 AST levels progress over time. 
 
10.5 STOPPING RULES FOR LIVER CHEMISTRY ELEVATIONS  
 
In the event of confirmed laboratory results meeting the following criteria, and the event is 
without an alternative explanation as discussed with the Sponsor Medical Monitor, or designee, 
dosing of a patient with Study Drug (X-82 or placebo) will be stopped permanently. Values that 
are not confirmed due to failure to retest or missing lab values will be presumed confirmed:  
 
1. ALT or AST > 8 x ULN, which is confirmed  
2. ALT 
_2 weeks  
3. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5  
4. ALT or AST > 3 x ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed and the new appearance (i.e., onset coincides with 
the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or concomitant eosinophilia (> ULN)  
10.6 DOSE MODIFICATIONS FOR TOXICITY 
 
Dose modifications will not be permitted in this study due to its masked design and the use of 
placebo tablets in both active and placebo treated subjects. 
11 STATISTICAL PLAN  
11.1 EFFICACY OUTCOMES AND HYPOTHESES 
nts who receive X-82 plus ivt anti-VEGF prn will 
have a non-inferior ETDRS visual acuity score after 52 weeks of treatment to the participants 
who receive ivt anti-VEGF monotherapy (ivt anti-VEGF prn plus placebo). 
11.1.1 Primary Efficacy Outcome 
The primary outcome is the change in visual acuity score from Day -1 to 52 Weeks after 
randomization in the study eye. 
11.1.2 Secondary Efficacy Outcome 
The secondary outcome is the number of ivt anti-VEGF injections during the first 52 Weeks after 
randomization in the study eye. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
11.1.3 Other Efficacy Outcomes 
 Proportion of subjects maintaining vision at 52 Weeks (losing < 15 letters on ETDRS 
chart) 
 Mean changes in CNV, total and active lesion sizes on FA at 52 Weeks 
 Mean changes in retinal thickness on SD-OCT at 52 Weeks 
 Other variables derived from the SD-OCT measurements 
 Time from Day 1 to first anti-VEGF injection 
 Conversion of fellow eye by 52 Weeks in subjects enrolled with unilateral disease 
11.2 SAFETY MEASURES 
Incidence of serious adverse events (SAEs) and adverse events (AEs), laboratory assessments 
and ECG.  All subjects who have received at least one dose of X-82 will be included in the safety 
population. 
 
The trial will specifically report the incidence of events considered to be related to treatment 
with tyrosine kinase inhibitors. 
11.3 SAMPLE SIZE JUSTIFICATION 
Based on similarly designed trials with this outcome in this population of previously treated 
AMD subjects, the SD of the change in visual acuity was assumed equal to 15. However, upon 
recalculation of the sample size, the correct SD to reproduce the required sample size is 14.3. 
With a sample size of 132 subjects, the trial will have at least 80% power to conclude the non-
inferiority of X-82 plus ivt anti-VEGF prn as compared to ivt anti-VEGF prn plus placebo in 
terms of visual acuity, using a non-inferiority margin equal to 9 ETDRS letters and a one-sided 
significance level of 0.05. This sample size was calculated assuming all doses are equally as 
efficacious, testing a difference in means for all 3 doses against placebo (i.e. using a 
randomization ratio of 3:1). Of note, this sample size calculation makes the conservative 
assumption that the dropout rate is as high as 20%, and that there is no treatment effect among 
dropouts; the required sample size is obtained by multiplying the randomized sample size by (1-
dropout rate)^2. If assuming an allocation ratio of 1:1 to better examine the power of a pairwise 
comparison, there is 80% power accounting for a dropout rate up to 20% if the true SD is 11. 
Based on previous studies, a SD of less than 14 is reasonable [25]. 
11.4 TESTING PROCEDURE 
Each dose will be tested against placebo using a Hochberg procedure. Let p1, p2 and p3 be the p-
values of the tests comparing each dose vs. placebo, with p1  p2  p3. Let  be the significance 
level appropriate for the analysis, provided by the 
-Fleming type Lan-DeMets alpha 
spending function, given the information fraction at the time of the analysis [26].  If p1 < , the 
three doses are non-inferior to placebo and the choice of dose must be based on other 
considerations. If p1 >  and p2 < /2, the doses corresponding to p2 and to p3 are non-inferior to 
placebo. If p1 > and p2 > /2 and p3 < /3, the dose corresponding to p3 is non-inferior to 
placebo. If p1 >  and p2 > /2 and p3 > /3, no dose can be declared non-inferior to placebo. 
11.5 RANDOMIZATION  
Randomization will be performed through an interactive web based system. Participants will be 
randomized to X-82 and placebo in a 1:1:1:1 ratio, using a dynamic minimization procedure 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
stratified by previous treatment schedule (every 6 weeks or less versus every 8 weeks) and anti-
VEGF therapy. The dynamic minimization will use a stochastic treatment allocation algorithm 
based on the variance method; this implementation of minimization guarantees that all treatment 
allocations are stochastic. 
11.6 ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population consists of all randomized subjects, grouped by treatment 
assigned by randomization. All efficacy analyses will be carried out on the ITT population. 
The Per-Protocol (PP) population consists of all randomized subjects who do not present a major 
protocol violation, grouped by treatment actually received. Major protocol violations will be 
adjudicated by a committee of experts who will not have access to treatment allocations, prior to 
the database lock. A sensitivity analysis using the PP population will be performed on the 
primary and secondary efficacy outcomes of the trial. 
The safety population will consist of all subjects treated, grouped by treatment group actually 
received.  All safety analyses will be performed on the safety population. 
11.7 INTERIM ANALYSES 
11.7.1 Interim Analysis 1 
An interim analysis is deemed necessary to enable the DSMB of the trial to perform a 
benefit/risk assessment including all efficacy and safety outcomes. This analysis will be 
conducted after 60 patients have reached their week 24 visit. The primary efficacy outcome of 
non-inferiority in change from randomization in VAS will be tested using 
-Fleming 
type Lan-DeMets alpha spending function, where the information fraction will be the percentage 
of patients that have completed their 52 week visit, though all available data will be used in the 
repeated measures model. There is no intention to stop early for efficacy, and the interim 
analysis will not be adequately powered to enable the DSMB to make such a recommendation. 
The spending function will however be used to adjust the significance level of the final analysis, 
given the interim analysis performed, should the trial continue unchanged. The adjustment has 
very little impact on the power of the trial, should the trial continue unchanged. If one or more of 
the doses of X-82 is stopped for any reason, the final analysis will make allowance for this 
adaptive design change by considering that the doses dropped would have failed to reach 
significance in the Hochberg procedure described in Section 11.4. This approach protects the 
significance level for each of the doses tested in the final analysis.  
-Fleming type Lan-DeMets beta spending function (using beta of 20%) will be used 
to assess futility at the time of the interim analysis. The futility boundary will be non-binding 
and, as such, will be used for information only. 
The available secondary efficacy outcome data of number of injections per year will also be 
presented to the DSMB at the time of interim analysis to guide decisions for dropping doses of 
X-82 or stopping the trial for futility or unfavorable risk/benefit ratio.   
11.7.2 Interim Analysis 2 
After the first interim analysis was conducted, it was determined an additional interim analysis 
will be necessary to enable the Sponsor to plan future trials of X82 in wet AMD or other 
indications. The second interim analysis will be reviewed by the DSMB and by a small group of 
individuals designated by the Sponsor.  


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
The second interim analysis is planned to be performed once approximately 90% of all subjects 
have reached their week 36 visit. The primary efficacy outcome will be tested using the O-Brien-
Fleming type Lan-Demets alpha spending function using the same approach as described in 
section 11.7.1. The calculation will take into consideration the first interim analysis, i.e. the first 
information fraction will be used in the calculation, along with the second information fraction. 
This accounts for the alpha that was spent at the first interim analysis, thus preserving the overall 
type I error of the entire trial. Since the purpose of this interim analysis is to fully explore the 
data to inform the design of a phase III trial, all endpoints, except the fluorescein angiogram 
endpoints, will be analyzed and a complete set of tables and figures will be produced for the 
interim as well as for the final analysis. If one or more of the doses of X82 is stopped for any 
reason, any hypothesis test result from the final analysis regarding those dropped doses will be 
considered exploratory. The Hochberg procedure described in Section 11.4 will be applied to all 
3 doses to preserve the significance level at final analysis for testing of the doses not dropped. 
 
11.8 STATISTICAL METHODOLOGY 
The final analysis of this trial will occur after all data from the first 52 Weeks are available. At 
this time, the data from the first 52 Weeks will be locked and the Sponsor will be unmasked. 
This section briefly describes the methods to be used to analyze the data. A Statistical Analysis 
Plan (SAP), to be written prior to unmasking the data, will describe the statistical analysis of the 
primary, secondary, and other outcomes in detail. Should the methods in the SAP differ from the 
description in this protocol, the methods in the SAP shall prevail. 
11.8.1 Efficacy 
The change in mean visual acuity (ETDRS BCVA at 4 m) in the X-82 group compared to the 
change in mean VA in the placebo group from Day -1 up to and including Week 52 visit will be 
analyzed using a restricted maximum likelihood (REML)-based repeated measures approach 
(Malinckrodt 2008).  
The analysis will use data from all scheduled post-baseline visits up to and including the 
outcome visit (52 weeks). The model will include the fixed, categorical effect of treatment visit, 
as well as the continuous, fixed covariate of baseline visual acuity score and baseline score-by-
visit interaction. 
An unstructured covariance matrix will first be used to model the within-subject errors, allowing 
flexibility in the variance and correlation estimates. If there are convergence problems in fitting 
the model, the following covariance structures will be used until the model converges (in order 
of decreasing flexibility): heterogeneous Toeplitz, first-order heterogeneous autoregressive, and 
first-order homogeneous autoregressive. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
The main comparison will be the test for the treatment effect at the endpoint visit (52 weeks) 
obtained by using an appropriate contrast of the treatment-related model parameters. 
The X-82 group will be compared to the placebo group with respect to the number of ivt anti-
VEGF injections up to and including week 52 by comparing the means calculated by an analysis 
of variance.  


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
The secondary efficacy outcome (number of injections per year) will be tested for any dose 
reaching significance for the primary outcome (visual acuity) at the time of final analysis; the 
test will use the same significance level for the secondary efficacy outcome as for the primary 
outcome (e.g. if =0.04 at the final analysis for the primary efficacy outcome, the secondary 
efficacy outcome will be tested at =0.04).  
Data from the other efficacy outcomes listed above will be summarized. Statistical analysis of 
these outcomes will be descriptive, with no correction for multiplicity. 
11.8.2 Safety 
Safety will be evaluated by assessing the incidence of adverse events (AEs), the incidence of 
serious adverse events (SAEs). 
 
AEs, SAEs, and other findings will be summarized by presenting the percentages of subjects 
with each event for each treatment group. When relevant, the time course of adverse events will 
be presented. 
 
12 SAFETY REPORTING  
Safety Analysis 
The safety of X-82 will be assessed through the collection and analysis of AEs, baseline 
medical conditions, results of the review of body systems, vital signs, complete ocular 
examination, and laboratory tests. Other protocol-specified tests that are deemed critical to the 
safety evaluation of the X-82 will be used to evaluate safety.  All safety assessments, including 
occurrence of AEs, intensity/severity, relationship to study drug, and treatment or action taken to 
resolve the event, will be performed by the evaluating physician. 
12.1 DEFINITIONS OF ADVERSE EVENTS 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease or 
laboratory or physiologic observations occurring in a person given a study drug or participating in 
a clinical study.  The event does not need to be causally related to the study drug.  An AE 
includes, but is not limited to, the following: 
Any clinically significant worsening of a pre-existing condition. 
An AE occurring from overdose (i.e. a dose higher than that indicated in the protocol) of a study 
drug, whether accidental or intentional. 
An AE that has been associated with the discontinuation of the use of a study drug. 
In order for the Sponsor to collect additional information about the clinically important 
laboratory or diagnostic tests (eg, blood, urinalysis, ECG) abnormalities, at a minimum, the 
following abnormalities should be captured on the AE CRF: 
 Any test result that meets the criteria for a serious adverse event (SAE). 
 Any test abnormality that suggests a disease and/or organ toxicity that is new or has 
significantly worsened. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 Any test abnormality that required the subject to have study medication discontinued 
or interrupted. 
 Any test abnormality that required the subject to receive specific corrective therapy, 
close observation, more frequent follow-up assessment, or further diagnostic 
investigation. 
Only clinically significant test abnormalities should be reported as AEs.  Determination of the 
clinical significance of test abnormalities is the responsibility of the Investigator.  In particular, 
mild hematology and chemistry abnormalities should be carefully considered for clinical 
relevance by the Investigator, as they are less likely to be of clinical significance as compared to 
moderate or severe abnormalities.  A clinical diagnosis, rather than the changes in laboratory or 
other assessment should be recorded on the CRF as appropriate (eg, anemia versus low 
hemoglobin value, bundle branch block rather than abnormal ECG). 
 Serious Adverse Events (SAE) 
Any adverse experience occurring at any dose that results in any of the following outcomes is 
classified as an SAE. 
 Results in death  
 Life threatening (see below for definition) 
 Requires subject hospitalization or prolongs subject hospitalization (see below for 
definition) 
 Results in persistent or significant disability/incapacity (see below for definition)  
 Results in a congenital anomaly/birth defect in a neonate/infant 
 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious AEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.  
Life-threatening refers to immediate risk of death as the event occurred per the reporter.  A life-
threatening experience does not include an experience, had it occurred in a more severe form, 
might have caused death, but as it actually occurred, did not create an immediate risk of death.  
For example, an allergic reaction resulting in angioedema of the face would not be life 
threatening, even though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can 
be fatal. 
Hospitalization is official admission to a hospital.  Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself considered 
a SAE.  In the absence of an AE, a hospitalization or prolongation of a hospitalization should not 
be reported by the PI.  This is the case in the following situations: 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (e.g., stent removal after surgery).  This should be recorded in 
the study file. 
 Hospitalization for survey visits or annual physicals falls in the same category. 
functions. 
A protocol-related adverse event is an AE occurring during a clinical study that is not related to 
the study drug, but is considered by the investigator or medical monitor to be related to the 
research conditions.  For example, a protocol-related AE may be an untoward event occurring 
during a washout period or an event related to a medical procedure required by the protocol. 
Other Reportable Information.  Certain information, while not meeting the above definition of an 
AE, is reportable to the sponsor as an SAE. This includes: 
 A case involving a pregnancy.  Information about use in pregnancy encompasses the 
entire course of pregnancy and delivery and perinatal and neonatal outcomes, even if 
there were no abnormal findings.  If a pregnancy is confirmed, the study drug must be 
discontinued immediately.  All reports of pregnancy must be followed for information 
about the course of the pregnancy and delivery, as well as the condition of the 
newborn.  When the newborn is healthy, additional follow-up is not needed. 
12.2 ADVERSE EVENT RECORDING AND REPORTING 
An AE or SAE can occur from the time that the subject signs the informed consent form to 30 
days, only AEs or SAEs determined by the investigator to be related to study drug are to be 
reported. All adverse events, regardless of severity and whether or not they are ascribed to the 
study treatment, will be recorded in the source documents.  All AEs and SAEs for subjects who 
are not screen failures will be recorded on the CRFs.  
The investigator must follow-up on all AEs, SAEs, and other reportable events until the events 
have subsided, returned to baseline, or in case of permanent impairment, until the condition 
stabilizes. If, in the opinion of the investigator, the AE or laboratory abnormality/ies are not 
likely to improve because of the underlying disease, the investigator must record his or her 
ent on the CRF.   
Any medication or other intervention necessary for the treatment of an adverse event must be 
recorded on the concomitant medication case report form.  
All AEs will be characterized by the following criteria: 
 Event term 
 Intensity or severity 
 Expectedness 
 Relationship to study treatment 
 Outcome 
 Treatment or action taken. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Whenever possible, recognized medical terms should be used when recording AEs. Colloquialisms 
and/or abbreviations should not be used.  
If more than one distinct adverse event occurs, each event should be recorded separately. 
However, if known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be 
recorded on the CRF rather than individual signs and symptoms (e.g., record congestive heart 
failure rather than dyspnea, rales, and cyanosis). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded as a separate AE. A diagnosis that is 
subsequently established should be reported as follow-up information. However, signs and 
symptoms that are considered unrelated to an encountered syndrome or disease should be 
recorded as individual AEs (e.g., if congestive heart failure and severe headache are observed at 
the same time, each event should be recorded as an individual AE). 
Adverse events occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause; a "primary" event, if clearly identifiable, should represent the most accurate 
clinical term to record as the AE event term.  For example: 
Orthostatic hypotension 
fainting and fall to floor
head trauma
neck pain 
The primary event is orthostatic hypotension and the sequelae are head trauma and neck pain. 
 
12.2.1 Classification of Adverse Events by Intensity/Severity 
All adverse events should be graded on a 3-point scale (mild, moderate, severe) for 
intensity/severity. These definitions are as follows: 
Mild:  
Transient discomfort; no medical intervention/therapy required and does 
not interfere with daily activities. 
Moderate:  
Moderate level of discomfort or concern with moderate limitation in daily 
activities; some assistance may be needed; minimal or no medical 
intervention/therapy required. 
Severe:  
Extreme discomfort and limitation in daily activities, significant assistance 
required; significant medical intervention/therapy required. 
There is a distinction between the severity and the seriousness of an adverse event. Severity is a 
measurement of intensity; thus, a severe reaction is not necessarily a serious adverse event 
(SAE). For example, a headache may be severe in intensity, but would not be serious unless it 
met one of the criteria for serious adverse events. 
12.2.2 Expectedness 
All AEs considered related to X-82 will be evaluated as to whether they are expected or 
unexpected.  Expectedness will be determined by the Sponsor. 
Expected (anticipated): 
An adverse event is expected when the nature, severity, 
or degree of incidence was previously described in the 
IB.   


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Unexpected (unanticipated): 
An adverse event is unexpected when the nature, 
severity, or degree of incidence was not previously 
described in the IB.  
12.2.3 Relatedness  
The study investigator will evaluate if the AE is related to X-82.  Relationship is defined in the 
following manner: 
Not related: Evidence indicates no plausible direct relationship to the study drug, such 
that: 
 A clinically plausible temporal sequence is inconsistent with the onset of the AE and 
drug administration; and/or 
 A causal relationship is considered biologically implausible 
 The AE can be attributed to concurrent/underlying illness, other drugs, or procedures. 
Related: Evidence indicates a reasonable temporal sequence of the event with the study 
drug administration exists, or that the association of the event with study drug 
administration is unknown and the event is not reasonably supported by other conditions, 
such that: 
 There is a clinically plausible time sequence between onset of the AE and study 
treatment administration; and/or 
 There is a biologically plausible mechanism for study treatment causing or 
contributing to the AE; and 
 The AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, 
or procedures. 
12.2.4 Outcome 
The clinical outcome of an AE will be characterized as follows: 
 
Resolved without sequelae 
 
Resolved with sequelae (specify) 
 
Ongoing (i.e. continuing at time of study discontinuation) 
 
Death. 
12.2.5 Treatment or Action Taken 
 None 
 Medical Intervention 
 Surgical Intervention 
 Other. 
12.3 SERIOUS ADVERSE EVENT REPORTING 
Serious Adverse Events (SAE) must be reported to the study sponsor as soon as possible and no 
later than 24 hours after the Investigator first learns of the event.  The SAE form is to be 
completed and submitted by email to Tyrogenex. For initial reports, investigators should record 
all case details that can be gathered within the reporting timeframe. Relevant follow-up 
information should be submitted to the study sponsor as soon as it becomes available and/or 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
upon request. For some events, the sponsor or its designee or the medical monitor may follow up 
with the site by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details deemed necessary to appropriately evaluate the event (e.g., hospital discharge summary, 
c
must be submitted to the study sponsor until the event has resolved or, in case of permanent 
impairment, until the event stabilizes and the overall clinical outcome has been ascertained. 
Pregnancy and symptomatic overdose should be reported following SAE reporting timelines. 
The SAE report should be sent to Tyrogenex via e-mail using the using the following contact 
information (during both business and non-business hours):  
 
 
SafetyFax@SynteractHCR.com  
 
 
To speak to the Medical Monitor directly regarding any SAE or medical concern contact: 
 
Medical Monitor: 
Dr. Stephan de la Motte 
Email:  Stephan.delaMotte@synteracthcr.com 
Direct: +49 89 12 66 80 2509  
 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the sponsor as soon as it is available; these reports should be submitted using 
the SAE Report Form.   
 
12.4 UNMASKING 
Treatment assignment will be masked to minimize bias in study assessments and monitoring.  
The randomization list will not be available to the subjects, study sites, or Sponsor until database 
lock. 
The drug supply vendor staff are authorized to receive the randomization list to facilitate drug 
packaging and monitor the site inventory.  The medical monitor will unmask treatment 
assignment only for individual subjects who have SAEs that are both unexpected and related in 
order to allow appropriate safety reporting to regulatory authorities. 
For emergency unmasking, when knowledge of the treatment assignment will impact the clinical 
management of the patient, the Investigator or designee will contact the IWRS prior to 
and the subject must be discontinued from study treatment. Whenever possible the Investigator 
is encouraged to contact the Sponsor or Medic
treatment assignment. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
13 STUDY COMPLETION 
13.1 SUBJECT DISCONTINUATION 
Subject participation is voluntary; any subject may discontinue participation in the study without 
prejudice or may be withdrawn from the study by the Investigator or Sponsor for the following 
reasons: 
 Pregnancy 
 Intolerable toxicity thought to be related 
 Patient request 
 Inability to comply with trial requirements 
 Conditions requiring treatment intervention not permitted by protocol 
 Intercurrent illness (investigators discretion) 
 Non-compliance/lost to follow-up 
 Discontinuation by Sponsor 
If the subject wishes to withdraw study consent, every effort will be made to encourage the 
subject to return to the study site for a final visit prior to withdrawing consent.   
13.2 LOST TO FOLLOW UP 
The study sites will attempt to follow-up on subjects who do not return for scheduled study 
examinations.  Sites must make a minimum of three documented attempts via telephone, email, 
or regular mail to contact the subject.  If the subject does not reply to any of these attempts, the 
site must send a letter by certified mail (with a request for notification of receipt of delivery) to 
the subject.  If a subject is non-responsive to these follow-up attempts, he/she will be considered 
to be lost to follow-up and the CRF will be updated to note lost to follow-up as the reason for 
discontinuation. 
13.3 EARLY SUBJECT TERMINATION / SUBJECT WITHDRAWAL 
Subjects who discontinue treatment early for any reason will be asked to undergo Week 52 
assessments.  These subjects will be followed for up to 30 days after the last dose of study 
medication for the development of new AEs. 
13.4 FOLLOW-UP OF SUBJECTS WITH ADVERSE EVENTS 
If any study subject has an adverse event at the time of completion, termination or withdrawal, 
the subject should be followed until resolution or stabilization of the adverse event. If in the 
opinion of the investigator, the AE or laboratory abnormality/ies are not likely to improve 
because of the underlying disease, the investigator must record his or her reasoning for this 
 
13.5 STUDY SUSPENSION, TERMINATION AND COMPLETION 
The Sponsor may suspend or terminate the study at any time for any reason. 
If the investigator suspends or terminates the study, the investigator will promptly inform the 
Sponsor and the IRB and provide them with a detailed written explanation.  The investigator will 
also return all study drug and other materials to the Sponsor.  Upon study completion, the 
investigator will provide the IRB with notice of closure. 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
14 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 COMPLIANCE STATEMENT, ETHICS AND REGULATORY COMPLIANCE 
This study will be conducted in compliance with the protocol, principles set forth in the 
Declaration of Helsinki (1998 version applicable for study sites in the EU), International 
Conference on Harmonization (ICH) Guideline E6 for Good Clinical Practice (GCP) 
(CPMP/ICH/135/95 Jan 1997), and the U.S. Code of Federal Regulations (CFR) Title 21, parts 
50, 54 56, and 312. 
14.2 IRB APPROVAL 
The study protocol, subject information and consent form, the Investigator Brochure, any subject 
diary card or written instructions to be given to the subject, available safety information, subject 
recruitment procedures (e.g., advertisements), information about payments and compensation 
be submitted to the IRB for ethical review and approval according to local regulations, prior to 
the study start.  The written approval should identify all documents reviewed by name and 
version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment.  The Investigator must submit and, where necessary, obtain approval from the IRB 
and/or Sponsor for all subsequent protocol amendments and changes to the informed consent 
document or changes of the investigational site, facilities or personnel.  The Investigator should 
notify the IRB of deviations from the protocol or serious adverse events occurring at the site and 
other adverse event reports received from the Sponsor in accordance with local procedures. 
Safety updates for X-82 will be prepared by the Sponsor or its representative as required, for 
submission to the relevant IRB. 
14.3 INFORMED CONSENT 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form. 
The informed consent form will be submitted for approval to the IRB that is responsible for 
review and approval of the study.  Each consent form must include all of the relevant elements 
currently required by the national regulatory body, as well as local county authority or state 
regulations. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications 
of participating in this trial, the candidate will be asked to give consent to participate in the trial 
by signing an informed consent form.  A notation that written informed consent has been 
 informed consent form, to 
re, will be provided by the investigator to the subject. 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
 
14.4 SUBJECT CONFIDENTIALITY 
the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws, 
as applicable.  HIPAA regulations require that, in order to participate in the trial, a subject must 
sign an authorization from the trial that he or she has been informed of following:  
 What protected health information (PHI) will be collected from subjects in this 
trial; 
 Who will have access to that information and why; 
 Who will use or disclose that information;  
 That health information may be further disclosed by the recipients of the 
information, and that if the information is disclosed the information may no 
longer be protected by federal or state privacy laws;  
 The information collected about the research trial will be kept separate from the 
records after the conclusion of the trial; 
 Whether the authorization contains an expiration date; and 
 The rights of a research subject to revoke his or her authorization.  
In the event that a subject revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e., that the subject is alive) 
at the end of their scheduled trial period. 
In compliance with ICH GCP guidelines, it is a requirement that the investigator and institution 
permit authorised representatives of Sponsor, the regulatory authorities and the IRB direct access 
dical records at the site for verification of trial-related 
procedures and data.  
Measures to protect confidentiality include: only a unique trial number and initials will identify 
subjects on the CRF or other documents submitted to the Sponsor.  This information, together 
with the subjec
or subject identification. Subject 
name will be kept on file by the Sponsor.  Subjects will be informed of their rights within the 
ICF. 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
15 RECORD KEEPING AND RETENTION 
15.1 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor (or its representative).  The written amendment must be reviewed and approved 
by the Sponsor, and submitted to the IRB for approval. 
Amendments specifically involving change to trial design, risk to subject, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the appropriate IRB. 
The amendment will be submitted formally to regulatory authorities by the Sponsor as 
applicable, after IRB approval and specifically when an increase to dosing or subject exposure 
and/or subject number has been proposed; or, when the addition or removal of an Investigator is 
necessitated. 
15.2 DOCUMENTATION REQUIRED TO INITIATE THE STUDY 
The Investigator must provide the Sponsor or its designee with the following documents prior to 
study initiation and retain a copy in the study file: 
 
A completed and signed Form FDA 1572.  If during the course of the study any 
changes occur that are not reflected on the 1572, a new 1572 form must be completed 
and returned to Sponsor/CRO for submission to the FDA. 
 
Current curriculum vitae and medical licenses (within 2 years) for the Principal 
Investigator. 
 
A copy of the original approval for conducting the study by the IRB.  Renewals, with 
continuance of the study, must be submitted at yearly intervals or as required by IRB 
policy. 
 
A copy of the IRB approved informed consent form. 
 
The signature page of this protocol signed and dated by the Principal Investigator. 
In addition to the documents listed above, the study site will also retain the following items: 
 Certifications and laboratory reference ranges for the central laboratory used for this 
study. 
 All original informed consent forms with required signatures 
 All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters) 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
 Clinical and non-clinical supply shipment forms 
 Copies of all correspondence pertaining to the study between the Sponsor or its 
designee and the site 
 Copies of all SAE reports submitted to the Sponsor or its designee 
 Study personnel signature log. 
15.3 STUDY DOCUMENTATION AND STORAGE 
All study-related records must be maintained for at least 2 years after a marketing application is 
approved for the drug; or if an application is not approved for the drug, until at least 2 years after 
shipment and delivery of the drug for investigational use is discontinued and FDA/health 
authorities or regulatory agencies have been notified.  The Sponsor will notify the principal 
investigator when records are no longer needed.  The investigator will not discard any records 
without notifying the Sponsor.  If the principal investigator moves from the current 
investigational site, the Sponsor should be notified of the name of the person who will assume 
responsibility for maintenance of the records at the investigational site or the new address at 
which the records will be stored.  The investigator will notify the Sponsor as soon as possible in 
the event of accidental loss or destruction of any study documentation 
15.4 DATA COLLECTION 
The electronic CRF (eCRF) is the primary data collection instrument for the trial.  eCRFs will be 
roughout the course of the 
trial.  In order to maintain confidentiality, only the study number, subject number and date of 
birth will identify the subject in the eCRF.  All data requested on the eCRF must be supported by 
s source documentation.   
Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the subjec
eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
All missing data must be explained.  When a required laboratory test, assessment, or evaluation 
eCRF, a note should be created 
v
must be corrected, and a note explaining the reason for change should be provided. 
The investigator will sign and date the subject eCRF casebook indicating that the data in the 
eCRF has been assessed.  Each completed eCRF will be electronically signed and dated by the 
PI, once all data for that subject is final. 
15.5 STUDY MONITORING, AUDITING, AND INSPECTING 
The investigator will permit monitoring, quality audits, and inspections by the government 
regulatory authorities, and the Sponsor or its representative(s) of all study related documents 
(e.g., source documents, regulatory documents, data collection instruments, case report forms).   


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
Study monitoring involves the following elements: 
 Tyrogenex personnel, or designee, may meet with investigators prior to the initiation of 
the study in order to review the adequacy of the subject population, facilities, and 
equipment with respect to the needs of the study, and to familiarize the investigator and 
support staff with the study protocol. 
 Tyrogenex personnel, or designee, may meet with the investigators at the time enrollment 
is initiated in order to ensure that subjects are being properly selected, that the methods 
described in the study protocol are thoroughly understood by the investigator, and that 
study data are being correctly recorded. 
 Tyrogenex personnel, or designee, may visit the clinical site at any time during the course 
of the study to review and/or collect completed case report forms. Additionally, telephone 
consultation will occur as necessary during the course of the study to ensure the proper 
progress and documentation of the study findings. 
15.6 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential.  The Sponsor reserves the right to 
release literature publications based on the results of the trial.  Results from the trial will be 
published/presented as 
 
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the trial.  The investigator acknowledges that the trial is 
part of a multi-center trial and agrees that any publication by the investigator of the results of the 
trial conducted at his/her research site shall not be made before the first multi-center publication.  
In the event there is no multi-center publication within fifteen (15) months after the trial has been 
completed or terminated at all trial sites, and all data has been received, the investigator shall 
have the right to publish its results from the trial, subject to the notice requirements described 
herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide 
the Sponsor thirty (30) days to review a manuscript or any poster presentation, abstract or other 
written or oral material which describes the results of the trial for the purpose only of 
determining if any confidential or patentable information is disclosed thereby.  If the Sponsor 
requests in writing, the investigator shall withhold any publication or presentation an additional 
sixty (60) days solely to permit the Sponsor to seek patent protection. 
 


Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
16 REFERENCES 
1.  Jager RD, Mieler WF, and Miller JW. Age-related macular degeneration. New Eng J Med 
2008;358:2606-17. 
2. Sickenberg M. Early detection, diagnosis and management of choroidal neovascularization in 
age-related macular degeneration: the role of ophthalmologists. Ophthalmologica. Journal 
international d'ophtalmologie. International J of Ophthalmol Zeitschrift fur Augenheilkunde 
2001;215:247-53. 
3. The Eye Diseases Prevalence Research Group. Epidemiology April 2004. 
4. Young RW. Pathophysiology of age-related macular degeneration. Survey of Ophthalmology 
1987;31:291-306. 
5. Seddon JM and Chen CA. The epidemiology of age-related macular degeneration. 
International Ophthalmol Clinics 2004;44:17-39. 
6. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical 
trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-
related macular degeneration and vision loss: AREDS report no. 8. Archives of Ophthalmol 
2001;119:1417-36. 
7. Davis MD, Gangnon RE, Lee LY, Hubbard LD, Klein BE, Ferris FL, Bressler SB, Age-
Related Eye Disease Study Group. The Age-Related Eye Disease Study severity scale for 
age-related macular degeneration: AREDS Report No. 17. Archives of Ophthalmol 
2005;123:1484-98. 
8. Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler 
SC, Klein R, Age-Related Eye Disease Study (AREDS) Research Group. A simplified 
severity scale for age-related macular degeneration: AREDS Report No. 18. Archives of 
Ophthalmol 2005;123:1570-74. 
9. Ghafour IM, Allan D, Foulds WS. Common causes of blindness and visual handicap in the 
west of Scotland. The British J Ophthalmol 1983;67:209-13. 
10. Oshinskie LJ. Age-related macular degeneration. Optometry clinics: the official publication 
of the Prentice Society 1996;5(1):25-53. 
11. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation 
and treatment in the macular photocoagulation study. Macular Photocoagulation Study 
Group. Archives of Ophthalmol 1991;109:1242-57. 
12. Gess AJ, Fung AE, Rodriguez JG. Imaging in neovascular age-related macular degeneration. 
Seminars in Ophthalmol 2011;26:225-33. 
13. Couch SM,  Bakri SJ. Review of combination therapies for neovascular age-related macular 
degeneration. Seminars in Ophthalmol 2011;26:114-20. 
14. Yuan A, Kaiser PK. Emerging therapies for the treatment of neovascular age related macular 
degeneration. Seminars in Ophthalmol 2011;26:149-55. 
15. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both 
pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. The Journal of 
Clin Invest 2003;111:1287-95. 


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16. Chung EJ, Yoo S, Lim HJ, Byeon SH, Lee JH, Koh HJ. Inhibition of choroidal 
neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib. 
The British J Ophthalmol 2009;93:958-63. 
17. Takahashi K, Saishin Y, Saishin Y, King AG, Levin R, Campchiaro PA. Suppression and 
regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. 
Archives of Ophthalmol 2009;127:494-9. 
18. Boyer DS. and Ophthotech Anti-PDGF in AMD Study Group, Combined Inhibition of 
Platelet Derived (PDGF) and Vascular Endothelial (VEGF) Growth Factors for the 
Treatment of Neovascular Age-Related Macular Degeneration (NV-AMD) - Results of a 
Phase 1 Study. Invest Ophthalmol Vis Sci 2009;50:1260. 
19. McLaughlin MM, et al., A Multi-Targeted Receptor Tyrosine Kinase Inhibitor for the 
Treatment of Neovascular AMD: Results of a Healthy Volunteer Safety and Tolerability 
Study of Pazopanib Eye Drops. Invest Ophthalmol Vis Sci 2009;5:5008. 
20. Diago T, Pulido JS, Molina JR, Collett LC, Link TP, Ryan EH Jr. Ranibizumab combined 
with low-dose sorafenib for exudative age-related macular degeneration. Mayo Clinic 
proceedings. Mayo Clinic 2008;83:231-34. 
21. Common Terminology Criteria for Adverse Events (CTCAE) v4.03, N.I.o.H. U.S. 
DEPARTMENT OF HEALTH AND HUMAN SERVICES, 2010. National Cancer Institute, 
Editor . 
22. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ, CATT Research  
Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. 
New Eng J Med 2011;364:1897-908. 
23. Lalwani GA, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular 
age-related macular degeneration: year 2 of the PrONTO Study. American Journal 
Ophthalmol 2009;148:43-58 e1. 
24. The CATT Reearch Group. The CATT study group. Ranibizumab and Bevacizumab for 
Neovascular Age-Related Macular Degeneration. N Engl J Med: 2011 Apr 28. 
 
25. Busbee BG, Ho AC, Brown DM, Heier JS, Suner IJ, Li Z, Rubio R, Lai P. Twelve-Month 
Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal 
Neovascular Age-related Macular Degenration. Ophthalmology. Mar 2013. Volume 120, 
Number 5 
26. DeMets DL, Lan KK, 1994, Interim analysis: The alpha spending function approach, 
Statistics in Medicine 13: 1341-1352 
 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
APPENDIX 1 SCHEDULE OF ASSESSMENTS 
 
Assessment 
 
Screening 
Visit 1 
Screening 
Visit 2 
Day -1 
Weeks 
4 to 48 
Week 52 
1 Month 
Post-
Treatment 
Follow-up 
Early 
Termination 
Visit Window 
Day -29 
 
Day -14 
(-7/+7) 
Day -1 
(+3) 
±7 days 
±7 days 
±7 days 
 
Informed Consent 
X  
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Med History/Con Meds 
X 
 
 
 
 
 
 
Ophthalmic History 
X 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
X 
X 
X 
Height and Weight 
 
X 
 
 
X* 
 
X* 
Labs and urinalysis 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic Sampling 
 
 
 
X
 
 
 
Pharmacogenetic Sampling 
 
 
 
 
X 
 
X 
ECG 
 
X 
 
X
X 
 
X 
Urine Pregnancy Test 
 
X 
 
 
 
 
 
Ophthalmic Exam 
 
X 
X 
X 
X 
X 
X 
IOP 
 
X 
X 
X 
X 
X 
X 
ETDRS Visual Acuity 
 
X 
X 
X 
X 
X 
X 
Study Medication 
Dispensed & Review of 
Dispensing Log  
 
 
X 
X 
 
 
 
FA & Photos (sent to IRC) 
 
X 
 
 
X 
 
X 
SD-OCT (sent to IRC) 
X 
X 
X 
X 
X 
X 
X 
Mandatory Anti-VEGF 
injection 
X 
 
X 
 
 
 
 
Anti-VEGF injection if 
required (prn) 
 
 
 
X 
X 
X** 
X 
AEs/ConMed changes 
X 
X 
X 
X 
X 
X 
X 
** Anti-VEGF therapy after week 52 will be standard of care for each ophthalmology practice 
* weight only 
1 Week 4, and Week 16 or Week 20, and Week 40, 44 or Week 48 only 
2 Week 4 12, 20, 28, 36, and 44  
3 Consent obtained from patients prior to any pre-
 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
APPENDIX 2 
DRUGS WITH A KNOWN RISK OF TORSADES DE POINTES AND/OR THAT PROLONG 
QT INTERVAL SHOULD BE USED WITH CAUTION. 
This is not a comprehensive list.  A complete list of drugs with a known risk of TdP may be found 
and is updated at the following web address: qtdrugs.org/medical-pros/drug-lists/drug-lists.htm 
 
Anesthetic 
Propofol (Diprivan®,  Propoven®) 
Sevoflurane (Ulane®, Sojourn®) 
Cocaine (Cocaine) 
Antiarrhythmics  
Amiodarone (Cordarone® ) (Pacerone® ) 
Disopyramide (Norpace®) 
Dofetilide (Tikosyn®) 
Ibutilide (Corvert®) 
Procainamide (Pronestyl®) (Procan®) 
Quinidine (Quinaglute®) (Cardioquin®) 
Sotalol (Betapace®) 
Dronedarone (Multaq) 
Flecainide (Tambocor), (Almartym), (Apocard), (Ecrinal), 
(Flecaine) 
 
Antibiotics 
Azithromycin (Zithromax®, Zmax®) 
Ciprofloxacin (Cipro ®),( Cipro-XR®), (Neofloxin®) 
Levofloxacin (Levaquin), (Tavanic) 
Clarithromycin (Biaxin®) 
Erythromycin (Erythrocin®) (E.E.S. ®) 
Gatifloxacin (ocular drops permitted) 
Moxifloxacin 
Sparfloxacin (Zagam®) 
 
Antihistamines 
Astemizole (Hismanal) 
Terfenadine (Seldane) 
 
 
Antipsychotics 
Chlorpromazine (Thorazine®) 


 
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Haloperidol (Haldol®) 
Levomepromazine (Nosinan), (Nozinan), (Levoprome) 
Levomethadyl (Orlaam) 
Droperiodol (Inapsine®, Droleptan®, Dridol®, 
Xomolix®) 
Mesoridazine (Serentil®) 
Pimozide (Orap®) 
Risperidone (Risperdal®) 
Thioridazine (Mellaril®) 
Ziprasidone 
 
Antidepressants 
Citalopram (Celexa®, Cipramil®) 
Escitalopram (Cipralex®, Lexapro®, Nexito®, Seroplex®, 
Elicea®, Lexamil®, Lexam® ) 
Antifungals (azoles) 
Fluconazole (Diflucan®, Trican®) 
Pentamidine (Pentam®) (NebuPent®) 
 
Antimalarials 
Chloroquine (Arelan®) 
Halofantrine (Halfan®) 
 
Antiemetics 
Ondansetron  (Zophran®) 
Domperidone  (Motilium®, Motillium®, Motinorm Costi®, 
Nomit®) 
Miscellaneous  
Arsenic trioxide (Trisenox®) 
Anagrelide (Agrylin), (Xagrid) 
Bepridil (Vascor®) 
Methadone (Dolophine), (Symoron), (Amidone), (Methadose), 
(Physeptone), (Hepadon) 
Cisapride (Propulsid®) 
Cilostazol (Pletal) 
Donepezil (Aricept®) 
Bepredil (Vasocor) 
Probucol (Lorelco) 


 
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APPENDIX 3  
COMMON P450 INHIBITORS, INDUCERS AND SUBSTRATES  
 
 The following tables from the FDA Drugs website describe medications and foods which are 
common inhibitors, inducers and substrates of P450, including CYP3A.  Potent (i.e., strong or 
moderate) CYP3A4 inhibitors or inducers should be avoided during this study. This list should not 
be considered all-inclusive.  Consult individual drug labels for specific information on a 
 
 
From FDA Drugs Website- inclusion of relevant CYP isozymes and categories 
 
Drug Development and Drug Interactions:  
Table of Substrates, Inhibitors and Inducers 
Classification of Inhibitors 
Table 5.  Classification of In Vivo Inhibitors of CYP Enzymes (1) (7/28/2011) 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm080499.htm 
 
 
CYP Enzymes 
Strong Inhibitors(2)  
-fold increase in AUC  
or > 80% decrease in CL 
Moderate inhibitors(3)  
-fold increase in AUC 
or 50-80% decrease in CL 
CYP3A 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice,(11) indinavir, 
itraconazole, ketoconazole,  
lopinavir/ritonavir, 
mibefradil,(12) 
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice,(11) 
imatinib, verapamil 
1. 
Please note the following:  This is not an exhaustive list.  For an updated list, see the 
following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm080499.htm 


 
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2. 
A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
substrate for that CYP by equal or more than 5-fold. 
3. 
A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC 
of a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.  
when a cert
 
12. Withdrawn from the United States market because of safety reasons. 
 
Table 6.  Classification of In Vivo Inducers of CYP Enzymes(1) (7/28/2011) 
CYP Enzymes Strong Inducers 
 
Moderate Inducers 
50-80% decrease in AUC 
CYP3A 
Avasimibe,(5) 
carbamazepine, 
phenytoin, rifampin, St. 
(3) 
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
(1) Please note the following:  This is not an exhaustive list.  For an updated list, see the following 
link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteraction
sLabeling/ucm080499.htm 
-dependent. 
(5) Not a marketed drug. 
 
 


 
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APPENDIX 4 
S 
 
The Sponsor is committed to: 
 
1. 
Complying with all applicable health authority regulations governing the conduct of 
clinical research studies, including the U.S. Food and Drug Administration. 
2. 
Protecting the rights, health, safety and welfare of study subjects. 
3. 
Informing the clinical investigators of any new information about the study which may 
affect the health, safety or welfare of the subjects, or may influence their decision to 
continue participation in the study. 
4. 
Providing the clinical investigators with the study protocol, and access to electronic Case 
Report Forms on which to document the study evaluation variables for each subject entered 
into the study. 
5. 
Providing the statistical analysis and study report writing resources necessary to complete 
reporting of the study results. 
6. 
Ensuring equity of consideration among all investigators in multicenter studies in all 
matters of publications, meeting presentations, etc. 
7. 
Certifying that IRB/EC approval of the protocol and Investigators Agreement will be 
completed prior to treatment at an investigational site. 
 


 
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APPENDIX 5 
FICATIONS AND RESPONSIBILITIES 
 
Each Investigator must be a licensed physician who has completed a residency or preceptorship in 
ophthalmology.  The Investigators have the following responsibilities: 
 
1. Subject Selection 
The Investigator is responsible for assuring that all subjects entering the study conform to the 
patient selection criteria. 
 
2. Informed Consent 
The Investigator is responsible for fully reviewing the nature of the study, the possible risks, and 
alternative treatments with prospective patients prior to their enrollment in the study.  The 
Investigator is responsible for obtaining written Informed Consent in compliance with 21 CFR 50 
for each patient, prior to enrollment in the trial.  A copy of the signed Informed Consent Form will 
be maintained in the patient's medical record. 
 
3. Institutional Review Board (IRB) Approval 
The Investigator must obtain approval for his participation in this protocol from the IRB/EC for the 
institution at which the procedure will be performed, prior to entering any patients in the study.  
The Informed Consent document to be used will also be submitted by the Investigator to the 
IRB/EC for approval prior to initiation of the study.  Assurance that the IRB/EC approval of the 
study protocol and Informed Consent has been obtained will be provided to the Sponsor prior to 
initiation of the study. 
 
4. Subject Evaluations and Data Reporting 
The Investigator is responsible for complying with the requirements of the study protocol, any 
amendment or clarifications as published by the study Sponsor (Tyrogenex) and performing the 
patient evaluations as described in the study protocol.  All information generated by the patient 
evaluation will be recorded using CRFs with access provided by the Sponsor.  Original laboratory 
reports will be retained by the Investigator, but as the results become available, they will be 
entered on appropriate CRFs.   
 
Investigator(s) will not deviate from the study protocol without prior approval of Tyrogenex unless 
protection of the health, safety or welfare of study subjects requires prompt action. 
 
 
 


 
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5. Record Retention 
The Investigator shall maintain all patient records for whichever of the following periods is 
shortest: 
a. A period of two years after the date on which the FDA approves the marketing of the drug 
for the purpose that was the subject of the study. 
b. A period of five years after the date on which the results of the study are submitted to the 
FDA in support of the marketing of the drug for the purpose that was the subject of the 
study. 
 
6. Investigational Material Accountability 
The Investigator must maintain accurate records of the receipt of all investigational material 
shipped by Tyrogenex, including the date, and identification numbers of the product received.  In 
addition, accurate records must be kept on the amount and date that investigational material, by 
identification number, was dispensed or returned to the Sponsor.  The Investigator must assure that 
study supplies be dispensed only to subjects enrolled in the study per the inclusion / exclusion 
criteria and under the direct supervision of the Investigator or his / her sub-investigators. 
 
Records of all investigational supplies received, used and returned must be kept by the 
Investigator.  All unused investigational supplies will be returned to the Sponsor as soon as 
practical upon completion of the trial.  Investigational material accounting procedures must be 
completed before the study is considered terminated. 


 
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APPENDIX 6 
DECLARATION OF HELSINKI 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964  
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 
(Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 
(Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, Korea, October 2008 
A.   INTRODUCTION 
1 The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
2 Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3 It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are dedicated 
to the fulfillment of this duty. 
4 The Declaration of Geneva of the WMA binds the physician with the words, "The health of my 
patient will be my first consideration," and the International Code of Medical Ethics declares 
that, "A physician shall act in the patient's best interest when providing medical care." 
5 Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6 In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 
7 The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must 
be evaluated continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 


 
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8 In medical practice and in medical research, most interventions involve risks and burdens. 
9 Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10 Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
B.   PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study. The protocol should describe arrangements for post-study access by study 
subjects to interventions identified as beneficial in the study or access to other appropriate care 
or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval to 
a research ethics committee before the study begins. This committee must be independent of 
the researcher, the sponsor and any other undue influence. It must take into consideration the 
laws and regulations of the country or countries in which the research is to be performed as 
well as applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee. 


 
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16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 
care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands to 
benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in the 
research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of 
the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given 
to the specific information needs of individual potential subjects as well as to the methods used 
to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the 
potential subject's freely-given informed consent, preferably in writing. If the consent cannot 
be expressed in writing, the non-written consent must be formally documented and witnessed. 


 
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25. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a research 
study that has no likelihood of benefit for them unless it is intended to promote the health of 
the population represented by the potential subject, the research cannot instead be performed 
with competent persons, and the research entails only minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research should be obtained as soon as possible from the subject or a legally 
authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the 
results of research. Authors have a duty to make publicly available the results of their research 
on human subjects and are accountable for the completeness and accuracy of their reports. 
They should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as 
well as positive results should be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest should be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE 
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 


 
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physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about 
the outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to withdraw 
from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, 
the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
 
  
 
 
 
 
 
 
 


 
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APPENDIX 7 ASSESSMENT OF VISUAL ACUITY 
Refraction and visual acuity (VA) measurements will be performed for all patients 
by trained vision examiners only. The name and certification number of the 
source document at each 
visit. VA examiners a
where possible to the 
previous VA testing results. Instead only the previous refraction should be made 
available. Refraction should be conducted prior to VA testing to obtain best-
corrected vision as described below. Best-corrected visual acuity (BCVA) is 
measured at all trial visits using standard charts, lighting, and procedures. Best 
correction is determined by careful refraction at that visit according to the standard 
protocol for refraction as described below. 
 
Equipment 
Refraction equipment required includes: 
1. Retroilluminated Light box and ETDRS 4 meter distance acuity chart set 
2. Trial lens frames 
3. Trial lens set with plus or minus cylinder lenses 
4. Jackson cross-cylinders of 0.25, 0.50, and 1.00 diopters 
5. Pinhole occluder 
6. Tissues or eye pads and tape 
7. A 1 meter rigid measuring stick 
 
Visual Acuity Charts 
Chart 1 is used for testing the VA of the RIGHT eye; Chart 2 for testing the LEFT 
eye; and Chart R (or 3) for refraction only. Patients should not be allowed to see 
any of the charts before the examination. 
 
Visual Acuity Lane and Visual Acuity Box 
A distance of 4 meters 
With the box light off, not more than 15 foot-candles of light (161.4 Lux) should 
fall on the center of the chart. To measure the amount of light, the room is set up for 
VA testing, but with the box light off. The light meter is placed at the fourth line 
from the top of the chart, with its back against the chart and the reading is taken. If 
more than one lane is available for testing VA, the VA of an individual patient 
should be measured in the same lane at each visit, if possible. If different lanes are 
used to test VA, they must each meet the same standards. 


 
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Retro illuminated ETDRS charts are used in this trial. The illuminator box will be 
either wall-mounted or mounted on a stand. The light box should be mounted at a 
height such that top of third row letter is 49 ± 2 inches from floor. 
 
The VA light box is equipped with two General Electric 20-watt fluorescent tubes 
and ballast. Each tube is partly covered by a 14-inch fenestrated sleeve, which is 
illumination over the testing chart. Because the illumination of fluorescent tubes 
diminishes by 5 percent during the first 100 hours and by another 5 percent during 
the next 2000 hours, new tubes should be kept on for 4 days (96 hours) 
continuously, and should be replaced once a year. 
 
A sticker should be placed on the back of the light box, indicating the date on 
which the present tubes were installed. A spare set of burned in bulbs should be 
available on site.  
 
Beginning Approximate Refraction 
ng refraction is determined by one of the 
following ways: 
 
require glasses for distance vision, then the beginning approximate refraction 
should be no lens correction or plano. 
If the 
glasses for distance viewing, the glasses should be measured using a focimeter, and 
these measurements are used for the beginning refraction. 
th or without correction, 
then retinoscopy, or auto refraction should be performed to determine the beginning 
approximate refraction. 
If the patient wears contact lenses for refraction, a notation should be 
made that the refraction was over contact lenses. It is suggested that the patient 
wear the contact lenses for future examinations. If the patient is not a regular 
contact lens wearer and wore the lenses by mistake, they should be removed and 
you should wait at least 30 minutes before beginning the refraction. The patient 
should be reminded not to wear contact lenses at subsequent visits.  
 


 
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Refractions are performed with either plus or minus cylinder power. Whichever 
cylinder type is used at baseline (minus or plus) must be used for all subsequent 
visits. Best correction results should be recorded on the sponsor provided worksheet 
which will be included in the source documents. At each follow-up visit, the 
results of the protocol refraction from the previous visit are used as the 
beginning approximate refraction. If the previous refraction is not available for 
some reason, the procedure described immediately above should be used. Whilst 
previous refraction results are made available at subsequent visits, previous VA 
results should not be visible to the examiners at subsequent testing, so that 
assessment of VA is masked to prior visual function.  
 
The charts used for measuring distance VA must NOT be used for refraction. 
Refraction for each eye should be performed at 4 meters 
measured at 4 meters on the refraction chart (Chart R or Chart 3) is worse than 
6/48 (20/160).If VA is worse than 6/48 (20/160) the eye is refracted at 1.0 meter. 
If during the refraction process at one meter, the patient is reading letters on the 
eighth line or lower line of the chart, the refraction should continue at 4 meters. 
Whenever a patient cannot read any letters on the top line of Chart R or Chart 3 at 
1.0 meter the vision should be checked with a pinhole to see whether reduced vision 
is due, at least in part, to a larger refractive error. If there is no improvement with 
the pinhole, then the eye is exempt from refraction. 
 
Patient Refraction 
 
Patient refraction allows one to determine the best correction for a patient to 
perform the VA tests. The 
 approach is used. Add minus diopter 
spherical corrections only when the patient is able to read at least one more 
letter on a line or a letter on a smaller line.  
 
Procedure 
1. Measure and record the distance vision of the eye being tested using Chart R 
while occluding the fellow eye. The fellow eye should be lightly patched with 
an eye pad or tissue and tape. Patients should be reminded to blink and 
encouraged to use eccentric fixation, or their side vision, when necessary. 
2. All refraction and vision testing must be done at 4 meters or 1 meter. Distance 
for 4 meters is 13 feet and 1.5 inches or 157.5 inches. The one meter distance is 
39 and 3/8 inches. 
3. All patients should be seated for testing. A rigid measuring device should be 
used to measure the distance from the patient to the chart if testing is done at 1 
meter. The distance is measured from the outer canthus to the center of the 


 
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second letter (left eye) or fourth letter (right eye) of the third line of the chart. 
For 4 meter testing, clear and permanent floor markings should be used to 
mark the distance for consistency. 
4. 
parallel to the anterior plane of the orbits and centered in front of the pupils. 
Adjust the lens cells for the proper distance from the cornea. Be sure the trial 
 
5. Occlude the left eye by lightly patching with an eye pad or tissue and tape. 
1. 
Place the spherical lens correction in the compartment closest to 
the eye. 
The cylindrical lens correction, if present, is placed in the compartment in front 
of the spherical correction. Adjust the axis. 
 
6. Spherical Correction: To determine the highest plus or least minus sphere, 
refract the right eye. The following refraction steps are recommended for VAs 
of 6/3 (20/10) to 6/24 (20/80) with the beginning approximate refraction. For 
VAs less than 6/24 (20/80), refer to the refraction table for the appropriate 
sphere and cylinder powers and testing distance (See summary below) and 
follow a similar procedure. Note: Whenever VA is improved to a higher range, 
refraction should be performed with the smaller sphere and cylinder powers 
given for the better VA level (See table at end of appendix). 
a) Hold a +0.50 sphere in front of the patie
looking at the smallest legible line on the VA chart. In these exact words, 
ask the patient, 
 
b) If the patient responds that the vision is worse or blurred, remove the 
+0.50 sphere from in front of the trial frame and go to Step 6d. 
c) If the patient responds better or no change, remove the +0.50 sphere from 
in front of the trial frame and replace the spherical lens in the trial frame 
with a spherical lens that is one-half diopter more positive .Continue this 
procedure by returning to Step 6a and repeating this process until a +0.50 
makes the vision worse or blurred and then go to Step 6d. 
d) Hold a -0.50 sphere 
 
e) Hold the -0.50 sphere in front of the eye. If the patient responds that the 
vision is better, ask the patient to read the VA chart. Only when the VA is 
improved, by at least one letter, may you increase the minus by 0.50 (or 
decrease the plus) and repeat Step 6d.Whenever VA is not improved, go to 
Step 6f. 
f) Remove the -0.50 sphere from in front of the eye and hold a +0.50 sphere in 


 
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unchanged, then return to Step 6c.Otherwise, go to Step 7. Spherical testing 
should always end with a plus lens. 
 
7. Cylinder Axis: To determine and refine the cylinder axis for PLUS cylinder, 
proceed as follows; (If minus cylinders are used, the appropriate technique 
using minus cylinders must be employed and minus cylinder must be used 
throughout the trial.) 
a) Have the patient look at a line which is either one or two lines larger than 
the smallest line the patient is able to read. Ask the patient to focus on a 
same letter throughout this procedure. 
b) If a cylinder is present in the beginning approximate refraction, then go to 
Step 7c. Otherwise, follow the option listed below to determine if cylinder 
may be needed. 
Testing for cylinder when there is none in the beginning 
approximate refraction: 
Place a +0.50 diopter cylinder with the positive axis first at 90 , 
then compare this to no cylinder; repeat this procedure for 180 , then 
45 , and 135  always comparing to no cylinder after each axis 
position. If the patient says that vision is improved at any one of the 
four axis positions, place a +0.50 cylindrical lens in the trial frame at 
the preferred axis and go to step 7c.If the patient prefers no cylinder 
at all four axis positions, then go to Step 9. 
c) Place the +0.25 diopter hand held cross-cylinder (for VA 6/3  6/24; 20/10-
20/80) first with the positive axis 45  to the right of the preferred cylinder 
axis (as determined above), and second with the positive axis 45  to the left 
blur their vision. The patient must choose the least blurred position, either 
equally good. 
d) 
move the axis of the cylinder in the trial frame 15  to the right or left and 
return to Step 7c.Otherwise, proceed to Step 7e. 
e) When one position is preferred over another, move the cylinder to the 
preferred positive axis position in the step sizes noted below and return to 
Step 7c.If no single position is better than another than go to Step 8. 
 
Cylinder Refinement suggested axis step 
sizes 
Cylinder 
 
Axis Step Sizes 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
Power  
<1.00D 
 
15o 
 
1.00 
to 
<2.00D 
 
 
10 o 
2.00 
to 
<3.00D 
 
 
5 o 
3.00 
to<5.00D 
 
 
3 o 
5.00 
to<8.00D 
 
 
2 o 
8. Cylinder Power: Cylinder power is refined by following the steps: 
a) Ask the patient to look at the smallest line that can be read on the VA chart. 
b) Test the cylinder power by placing the 0.25 diopter cross-cylinder (for 
vision of 6/3 - 6/24; 20/10-20/80) first with the positive axis and second 
with the negative axis coincident with the cylinder axis. Ask the patient, 
choice of neither. 
c) If the patient prefers the minus axis coincident with the cylinder axis, the 
total power of the correcting plus cylinder is reduced by 0.25 diopter. 
Repeat the process until the patient cannot choose one of the cross cylinder 
positions over the other. If the patient indicates a change that would 
introduce negative cylinder power, remove all cylinder power and continue 
testing for positive cylinder power at an axis 90 away from the previous 
axis. Otherwise go to Step 8d. 
d) If the patient prefers the plus axis coincident with the cylinder axis, increase 
the power of the cylinder by 0.25 diopters and return to Step 8b.Otherwise 
proceed to Step 8e. 
e) When the patient feels that both positions are equally bad or good, and the 
cylinder power in the trial frame has changed by more than 0.50 diopter, 
return to Step 7c and re-check the axis if necessary. Otherwise, proceed to 
Step 9. 
Note: If the cylinder is changed by more than 0.50 diopter, the spherical 
equivalent should be maintained.(For each 0.50 plus CX increase, add 
0.25 to the sphere, for each 0.50 minus CX increase, add +0.25 to the 
sphere). 
9. Spherical Correction Refinement: Recheck, or 
 the power of the 
sphere by adding+0.25 and -0.25 spheres and changing the spherical power by 
0.25 diopter increments of the appropriate sign until the patient cannot detect 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
any improvement in vision. As a reminder, minus sphere should only be 
added if the patient can read additional letters and spherical testing should 
always begin and end with a plus lens. 
10. Record the lens corrections obtained by patient refraction for the right eye on 
the examination form in the section for VA measurements as the corrections 
obtained by protocol refraction for the right eye. 
11. Repeat the entire process (Steps 1-10) for the left eye and record the refraction 
result on the VAE worksheet. 
 
Best Corrected Visual Acuity Measures 
 
As a reminder, Charts 1, 2, and R (or 3) are used for testing the right 
eye, left eye, and refraction, respectively. Patients should not see the charts until the 
test begins.  
The lens correction from the patient refraction should be in the trial 
frame worn by the patient. 
All eyes must be tested at 4 meters first, even if the refraction was 
performed at 1 meter 
The patient should be seated comfortably directly in front of the chart 
so that the eyes remain at the 4 meter distance. Testing always begins with the right 
eye. The fellow should be occluded with a folded tissue or eye pad lightly taped 
over the eye behind the trial frame serves as an effective occluder that allows 
eccentric fixation without inadvertent use of the covered eye. After testing the right 
eye, occlusion of the right eye should be done BEFORE Chart 2 is put up for testing 
the left eye. 
The patient is asked to read the letters slowly, approximately one letter 
per second. The patient should be told that only one chance is given to read each 
letter, but they may change their mind before moving to the next letter. If the patient 
is unsure about the identity of the letter, then the patient should be encouraged to 
guess. 
The patient should begin by reading the top line of the chart and 
continue reading every letter on each smaller line, from left to right on each line. 
The patient should be encouraged to continue reading even if making mistakes. 
Each letter read is counted. The examiner circles every correct letter read and totals 
each line and the whole column (0 if no letters are correct) on the data collection 
form. An X is put through letters read incorrectly. Letters, for which no guess was 
attempted, are not marked. When a patient reaches a level where he/she cannot 
guess, the examiner may stop the test provided that the patient has made errors on 
previous guesses, which is a clear indication that the best VA has been obtained. 
When a patient cannot read at least 20 letters on the chart at 4.0 meters, 
the patient is tested at 1.0 meter. The distance from the patient to the chart should 
be measured again using the rigid one meter stick. The distance is measured from 
the outer canthus to the center of the fourth letter (right eye) or the second letter 
(left eye) of the third line of the chart. The spherical correction in the trial frame 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
should be changed by adding +0.75 to correct for the closer test distance. The 
patient may fixate eccentrically or turn or shake his/her head to improve VA. 
Particular care should be taken to make sure the patient does not move forward 
when testing at 1 meter. The patient should be reminded to blink. 
The examiner should not tell the patient if a letter was identified 
correctly. The patient may be encouraged by neutral comments, such 
 
The examiner should not stand close to the chart during testing. 
Attention should be focused on the patient and the data collection form. If the 
patient has difficulty locating the next line to read, the examiner may go up to the 
chart and point briefly to the next line to be read, but then must move away from 
the chart. 
When 20 or more letters are read at 4 meters the VA score for that eye 
is recorded as the number of letters correct plus 30 (refer to the VA worksheet) The 
patient gets credit for the 30 1M letters even though they did not have to read them. 
Otherwise, the VA score is the number of letters read correctly at 1.0 meter plus the 
number, if any, read at 4M.If no letters are read correctly at either 4.0 meters or 1 
meter, then the VA score is recorded as 0. 
 
Testing for Count Fingers Vision, Hand Motion Vision and Light 
Perception/No Light Perception (NLP) Vision 
one meter then the 
light perception should be evaluated. 
 
Testing for Count Fingers Vision 
held steady at a distance of two feet directly in front of the eye being examined. The 
fellow eye is completely occluded with a patch on the face. A light should be shown 
presented in random order and repeated 5 times. Eccentric fixation, if present, 
should be encouraged. If the patient correctly identifies three of the five 
presentations, then count fingers vision is noted. If not, then the patient must be 
tested for hand motion vision. 
 
Testing for Hand Motion Vision 
directly in front of the eye being examined. The fellow eye should be occluded with 
hand f
-and-
down direction (vertically) or in a side-to-side direction (horizontally) at a constant 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017 
 
 
 
 
speed of approximately one back and forth presentation per second. The patient is 
instructed th
times. Three out of five correct responses indicate that hand motion vision is 
present. If the patient does not correctly identify three of five presentations, then 
you must test for light perception. 
 
Testing for Light Perception/No Light Perception Vision 
Light perception should be tested with an indirect ophthalmoscope in a darkened 
room. The fellow eye should be completely patched and also covered by the 
the rheostat set at maximum voltage. From that distance the beam should be 
st four times, and the patient should be 
asked to respond when he or she sees the light. If the examiner is convinced that the 
 




 
Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
APPENDIX 8: AREDS LENS GRADING PROCEDURE 
Overview 
The AREDS Clinical Lens Grading Procedure is a simple system for grading the presence and 
severity of nuclear, cortical and posterior subcapsular lens opacities at the slit-lamp.  The validity 
of the grading results is dependent upon careful adherence to the grading procedures by the 
examiner.  The grading procedures listed below should be read before any grading is done. 
 General Instructions 
 Dilate pupils to at least 5 mm diameter 
 Use slit lamp with ~10X magnification 
 Use brightest beam intensity 
 Grade nuclear, cortical and PSC opacities using the 8X10 glossy print of the 
 
 which has been 
supplied to you 
 Nuclear opacity  
 Orient beam at 45° to viewing axis 
 Adjust slit beam to standard parameters: 8 mm height and 0.3 mm width 
 Compare opalescence of nucleus with that in standard photos 
 Cortical and PSC opacities 
 Select wide slit beam setting optimum for retro-illumination of lens 
 Visualize lens opacities against red fundus reflex background 
 Count only opacities definitely visible against red reflex 
 Mentally combine all cortical opacities into one contiguous area 
 Compare total opacity area with that in standard photos 
 Classify each opacity with scale defined by 3 standard photos 
 Select nearest half-step which is 
 Similar to standard or between two standards 
 Obviously less than mildest standard or greater than most severe 


 
Protocol X82-OPH-201, Version 10, 12 Sep 2017  
 
 
 
AREDS GRADING SCALE 
Grade 
Description of Opacity 
>1 
No Opacity or less than Standard 1 
1.0 
Same as Standard 1 
1.5 
More than Standard 1 but less than Standard 2 
2.0 
Same as Standard 2 
2.5 
More than Standard 2 but less than Standard 3 
3.0 
Same as Standard 3 
>3 
More than Standard 3 
 
 



SAP_001.pdf: 
Signature Page for X82-OPH-201_SAP
Study X82-OPH-201 v4.0
Signature Page for X82-OPH-201_SAP
Study X82-OPH-201 v4.0
eSignature for Approval
Dan Salazar
Sponsor
11-Sep-2017 18:20:43 GMT+0000
eSignature for Approval
Michael Hussey
IDDI Department Manager
11-Sep-2017 19:30:35 GMT+0000
eSignature for Approval
Kate Fisher
Author
11-Sep-2017 20:38:08 GMT+0000
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Confidential 
Tyrogenex 
Version : FINAL 
Page 1 of 34 
X82-OPH-201 
Date: 11 September 2017 
 
 
 
Statistical Analysis Plan 
 
 
 
Sponsor:  
TYROGENEX 
Protocol Title:  
A 
RANDOMIZED, 
DOUBLE-MASKED, 
PLACEBO-
CONTROLLED, 
DOSE-FINDING, 
NON-INFERIORITY 
STUDY OF X-82 PLUS PRN ivt anti-VEGF COMPARED TO 
PRN ivt anti-VEGF MONOTHERAPY IN NEOVASCULAR 
AMD 
Study Code: 
X82-OPH-201 
 
 
 
For IDDI: 
Author: Kate Fisher, Senior Biostatistician, Biostatistical Services 
Author: Michael Hussey, Manager, Biostatistical Services 
 
 
For Sponsor: 
Reviewer: Jen Cerami, Clinical Research Manager 
Approver: Daniel E. Salazar, Ph.D., Senior Vice President, Development 
 
 
 
 
 
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X82-OPH-201 
Date: 11 September 2017 
 
Revision History 
Version 
Summary of Revisions 
1.0 
N/A 
2.0 
Updated footer with correct date (from 28 November 2016 to 13 January 2017) 
and changed Version: ‘DRAFT’ to ‘FINAL’. 
3.0 
Changed main analysis set from PP to ITT. Added an additional other efficacy 
outcome: Proportion of patients maintaining vision at week 52 (losing <15 letters
on ETDRS chart). Changed Daniel E. Salazar from reviewer to approver. 
4.0 
Added a second interim analysis. Added other efficacy outcomes for subjects 
enrolled with unilateral disease: Conversion of fellow eye by 52 Weeks, change 
in visual acuity, and number of injections per year at 52 weeks in fellow eye. 
Defined major deviation criteria for exclusion from Per Protocol Population. 
Specified other OCT variables. Added safety outcome: Cardiovascular adverse 
events of interest.   
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Statistical Analysis Plan 
 
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Tyrogenex 
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Date: 11 September 2017 
Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 5 
2. 
INTRODUCTION ........................................................................................... 6 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................ 6 
3.1 
Study Objective ....................................................................................... 6 
3.1.1 
Primary Efficacy Outcome................................................................... 6 
3.1.2 
Secondary Efficacy Outcome ............................................................... 6 
3.1.3 
Other Efficacy Outcomes .................................................................... 6 
3.1.4 
Safety Outcomes ............................................................................... 7 
3.2 
Study Design ........................................................................................... 7 
3.3 
Sample Size Justification ........................................................................... 9 
3.4 
Interim Analyses ...................................................................................... 9 
3.4.1 
Interim Analysis 1 ............................................................................. 9 
3.4.2 
Interim Analysis 2 ............................................................................. 9 
4. 
GENERAL ANALYSIS DEFINITIONS ............................................................ 10 
4.1 
Definition of Populations ......................................................................... 10 
4.1.1 
Intention-To-Treat (ITT) Population ................................................... 10 
4.1.2 
Per Protocol (PP) Population ............................................................. 10 
4.1.3 
Safety (SAF) Population ................................................................... 11 
4.2 
Definition of Baseline .............................................................................. 11 
4.3 
Study Completion .................................................................................. 11 
4.4 
Calculated Variables ............................................................................... 11 
4.4.1 
Study Day ...................................................................................... 11 
4.4.2 
Duration ........................................................................................ 11 
4.5 
Handling of Unscheduled and Early Withdrawal Visits ................................. 12 
4.5.1 
Visual Acuity Outcome ..................................................................... 12 
4.5.2 
Safety Outcomes ............................................................................. 12 
4.6 
Partial Dates ......................................................................................... 13 
4.7 
Methods To Be Used For Handling Missing Data ......................................... 13 
4.7.1 
Descriptive Analyses ........................................................................ 13 
4.7.2 
Inferential Analyses ......................................................................... 13 
4.8 
Additional Analyses not Listed in the Protocol ............................................ 13 
5. 
STUDY SUBJECTS ....................................................................................... 13 
5.1 
Disposition of Subjects ........................................................................... 13 
5.2 
Protocol Deviations ................................................................................ 14 
5.3 
Inclusion and Exclusion Criteria ............................................................... 14 
5.4 
Out of Window Visits .............................................................................. 14 
5.5 
Re-treatment Criteria Adherence ............................................................. 14 
5.6 
Food and Alcohol Intake ......................................................................... 14 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 14 
7. 
PRIOR AND CONCOMITANT TREATMENT .................................................... 16 
7.1 
Prior and Concomitant Medications ........................................................... 16 
7.2 
Prior and Concomitant Surgeries/Procedures ............................................. 16 
8. 
EFFICACY EVALUATION ............................................................................. 16 
8.1 
Control of Type I Error ............................................................................ 17 
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Date: 11 September 2017 
8.2 
Analysis of Primary Efficacy Outcome ....................................................... 17 
8.2.1 
Best Corrected Visual Acuity (BCVA) .................................................. 17 
8.2.2 
MRM Model ..................................................................................... 17 
8.2.3 
Variance-Covariance Structure .......................................................... 18 
8.2.4 
Testing Procedure ........................................................................... 19 
8.2.5 
Data Displays ................................................................................. 19 
8.3 
Analysis of Secondary Efficacy Outcome ................................................... 19 
8.4 
Analysis of Other Efficacy Outcomes ......................................................... 20 
8.4.1 
Analysis of Maintaining Vision at Week 52 .......................................... 20 
8.4.2 
Imaging-Based Outcomes ................................................................ 20 
8.4.3 
Supportive Analysis of Time to First anti-VEGF Injection ....................... 21 
8.4.4 
Analyses in Fellow Eye ..................................................................... 21 
8.5 
Sensitivity Analyses ............................................................................... 21 
9. 
SAFETY EVALUATION ................................................................................. 22 
9.1 
Extent of Exposure ................................................................................. 22 
9.1.1 
Exposure to X-82 ............................................................................ 22 
9.1.2 
Exposure to anti-VEGF Treatment ..................................................... 23 
9.2 
Adverse Events ...................................................................................... 23 
9.3 
Deaths and Serious Adverse Events ......................................................... 24 
9.4 
Clinical Laboratory Determination ............................................................ 25 
9.5 
Vital Signs, Physical Findings and Other Observations Related to Safety ....... 26 
9.5.1 
Vital Signs ...................................................................................... 26 
9.5.2 
Ophthalmic Examination .................................................................. 26 
9.5.3 
Tonometry ..................................................................................... 26 
9.5.4 
ECG ............................................................................................... 27 
10. 
REFERENCES .......................................................................................... 27 
11. 
LIST OF TABLES/GRAPHS/LISTINGS ..................................................... 28 
11.1 
List of Statistical Tables .......................................................................... 28 
11.2 
List of Graphs ........................................................................................ 33 
11.3 
List of Derived Data Listings .................................................................... 34 
 
 
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Tyrogenex 
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Date: 11 September 2017 
1. 
List of Abbreviations and Definition of Terms 
 
Abbreviation 
Term 
 
AE 
Adverse Event 
 
AMD 
Age-related Macular Degeneration 
 
ATC 
Anatomic Therapeutic Chemical Classification 
 
BCVA 
Best Corrected Visual Acuity 
 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
 
CNV 
Choroidal Neovascularization 
 
DSMB 
Data and Safety Monitoring Board 
 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
 
FA 
Fluorescein Angiography 
 
ICH 
International Conference on Harmonization 
 
IOP 
Intraocular Pressure 
 
IRC 
Independent Reading Center 
 
IVT 
Intravitreous 
 
MAR 
Missing at Random 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MNAR 
Missing Not at Random 
 
MRM 
Model for Repeated Measures 
 
NCI-CTC 
National Cancer Institute – Common Terminology Criteria 
 
NCMV 
Neighboring-Case Missing Value 
 
OS 
Oculus Sinister 
 
OD 
Oculus Dexter 
 
OU 
Oculi Uterque 
 
PT 
Preferred Term 
 
REML 
Restricted Maximum Likelihood 
 
SAE 
Serious Adverse Event 
 
SAP 
Statistical Analysis Plan 
 
SD 
Standard Deviation 
 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
 
SOC 
System Organ Class 
 
TEAE 
Treatment-Emergent Adverse Event 
 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 
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Date: 11 September 2017 
2. 
Introduction 
This statistical analysis plan (SAP) was written to detail the planned statistical 
analyses of efficacy and safety data for the primary analysis of clinical trial X82-
OPH-201 conducted in the United States. The ICH guideline E3 “Structure and 
Content of Clinical Study Reports” was used as a guide to the writing of the plan. 
This statistical analysis plan does not describe the analyses of safety which will be 
conducted for Data and Safety Monitoring Board (DSMB) review. Please refer to the 
DSMB charter for more information on these analyses.  
This statistical analysis plan is based on the Study Protocol Version 10. 
3. 
Study Design and Objectives 
3.1 
Study Objective 
The objective of this study is to evaluate the efficacy and safety of X-82 at three 
doses, in subjects with wet AMD as determined by comparison of the mean ETDRS 
visual acuity scores at Week 52.  
3.1.1 
Primary Efficacy Outcome 
The primary outcome is the change in visual acuity score from Day -1 to 52 Weeks 
after randomization in study eye. 
3.1.2 
Secondary Efficacy Outcome 
The secondary outcome is the number of ivt anti-VEGF injections during the first 52 
Weeks after randomization in study eye.  
3.1.3 
Other Efficacy Outcomes 
 
Proportion of subjects maintaining vision at 52 Weeks (losing <15 letters 
from Day -1 on ETDRS chart) in study eye and fellow eye. 
 
Mean changes in CNV, total and active lesion sizes on FA from Day -1 at 52 
Weeks in study eye and fellow eye 
 
Mean changes in retinal thickness on SD-OCT from Day -1 at 52 Weeks in 
study eye and fellow eye 
 
Other variables derived from the SD-OCT measurements in study eye and 
fellow eye 
 
Time from Day 1 to first anti-VEGF injection in study eye 
 
Conversion of fellow eye by 52 Weeks in subjects enrolled with unilateral 
disease  
 
Mean change in visual acuity score from Day -1 to 52 Weeks after 
randomization in fellow eye 
 
Mean change in visual acuity score from Day -1 to 52 Weeks after 
randomization in fellow eye of subjects enrolled with unilateral disease  
 
Number of ivt anti-VEGF injections during the first 52 Weeks after 
randomization in fellow eye 
 
Number of ivt anti-VEGF injections during the first 52 Weeks after 
randomization in fellow eye of subjects enrolled with unilateral disease 
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3.1.4 
Safety Outcomes 
 
Incidence of serious adverse events (SAEs) and adverse events (AEs) 
 
Ophthalmic variables (including IOP) 
 
Laboratory Assessments 
 
Vital Signs 
 
ECG 
 
Cardiovascular adverse events of interest  
3.2 
Study Design 
This is a randomized, double-masked, placebo-controlled study in which at least 
132 subjects will be randomized to receive 50 mg, 100 mg, 200 mg of X-82, or 
matching placebo tablets daily for 52 weeks. Subjects requiring frequent injections 
of ivt anti-VEGF (an interval no greater than 8 weeks) and with the presence of any 
macular fluid and macular thickness on SD-OCT will receive an injection of anti-
VEGF during Screening Visit 1 and return for Screening Visit 2 to document a 
reduction in macular fluid or macular thickness, which will be confirmed by the 
Independent Reading Center (IRC). If a subject does not demonstrate any 
reduction of macular fluid or macular thickness at Screening Visit 2 and the 
investigator believes the subject may not have had enough time to achieve such a 
reduction, subjects may be re-screened for Screening Visit 2 as long as the visit 
occurs within the protocol specified window [Day -14 (+/- 7 days)]. Subjects with  
a reduction in macular fluid or macular thickness will undergo additional screening 
assessments and be enrolled into the study. Subjects will receive a further injection 
of anti-VEGF at Day -1 and start study treatment the following day. All subjects will 
remain on study treatment for 52 weeks and be assessed for the need for further 
injections of anti-VEGF every 4 weeks for that period.  
 
 
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Date: 11 September 2017 
Schedule of Assessments 
Assessment 
Screening 
Visit 1 
Screening 
Visit 2 
Day 
-1 
Weeks 
4 to 48 
Week 
52 
1 Month 
Post-
Treatment 
Follow-up 
Early 
Termination 
Visit Window 
Day -29 
Day -14 (-
7/+7) 
Day 
-1 
(+3) 
±7 days 
±7 
days 
±7 days 
 
Informed 
Consent 
X3 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Med History/Con 
Meds 
X 
 
 
 
 
 
 
Ophthalmic 
History 
X 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
X 
X 
X 
Height and 
Weight 
 
X 
 
 
X* 
 
X* 
Labs and 
Urinalysis 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic 
Sampling 
 
 
 
X1 
 
 
 
Pharmacogenetic 
Sampling 
 
 
 
 
X 
 
X 
ECG 
 
X 
 
X2 
X 
 
X 
Urine Pregnancy 
Test 
 
X 
 
 
 
 
 
Ophthalmic 
Exam 
 
X 
X 
X 
X 
X 
X 
IOP 
 
X 
X 
X 
X 
X 
X 
ETDRS Visual 
Acuity 
 
X 
X 
X 
X 
X 
X 
Study Medication 
Dispensed & 
Review of 
Dispensing Log 
 
 
X 
X 
 
 
 
FA & Photos 
(sent to IRC) 
 
X 
 
 
X 
 
X 
SD-OCT (sent to 
IRC) 
X 
X 
X 
X 
X 
X 
X 
Mandatory anti-
VEGF Injection 
X 
 
X 
 
 
 
 
anti-VEGF 
injection if 
required (prn) 
 
 
 
X 
X 
X** 
X 
AEs/ConMed 
Changes 
X 
X 
X 
X 
X 
X 
X 
** Anti-VEGF therapy after week 52 will be standard of care for each ophthalmology practice 
* weight only 
1 Week 4, Week 16 or Week 20, and Week 40, 44 or Week 48 only 
2 Week 4 only 
3 Consent obtained from patients prior to any pre-screening which results in the change of the patients’ 
standard of care or management  
 
 
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3.3 
Sample Size Justification 
At least one hundred and thirty two (132) subjects will be randomized to 50, 100, 
200 mg X-82 or placebo qd in a 1:1:1:1 ratio (33:33:33:33 subjects) at 35 to 45 
sites in the US.  
Based on similarly designed trials with this outcome in this population of previously 
treated AMD subjects, the SD of the change in visual acuity was assumed equal to 
15. However, upon recalculation of the sample size, the correct SD to reproduce 
the required sample size is 14.3. With a sample size of 132 subjects, the trial will 
have at least 80% power to conclude the non-inferiority of X-82 plus ivt anti-VEGF 
prn as compared to ivt anti-VEGF prn plus placebo in terms of visual acuity, using a 
non-inferiority margin equal to 9 ETDRS letters and a one-sided significance level 
of 0.05. This sample size was calculated assuming all doses are equally as 
efficacious, testing a difference in means for all 3 doses against placebo (i.e. using 
a randomization ratio of 3:1). Of note, this sample size calculation makes the 
conservative assumption that the dropout rate is as high as 20%, and that there is 
no treatment effect among dropouts; the required sample size is obtained by 
multiplying the randomized sample size by (1-dropout rate)^2. If assuming an 
allocation ratio of 1:1 to better examine the power of a pairwise comparison, there 
is 80% power accounting for a dropout rate up to 20% if the true SD is 11. Based 
on previous studies, a SD of less than 14 is reasonable [Busbee,2013].  
3.4 
Interim Analyses 
3.4.1 
Interim Analysis 1 
An interim analysis is deemed necessary to enable the DSMB of the trial to perform 
a benefit/risk assessment including all efficacy and safety outcomes. This analysis 
will be conducted after 60 patients have reached their week 24 visit. The primary 
efficacy outcome of non-inferiority in change from randomization in VAS will be 
tested using an O’Brien-Fleming type Lan-DeMets alpha spending function, where 
the information fraction will be the percentage of patients that have completed 
their 52 week visit, though all available data will be used in the repeated measures 
model [DeMets, 1994]. There is no intention to stop early for efficacy, and the 
interim analysis will not be adequately powered to enable the DSMB to make such 
a recommendation. The spending function will however be used to adjust the 
significance level of the final analysis, given that the interim analysis is performed, 
should the trial continue unchanged. The adjustment has very little impact on the 
power of the trial, should the trial continue unchanged. If one or more of the doses 
of X82 is stopped for any reason, the final analysis will make allowance for this 
adaptive design change by considering that the doses dropped would have failed to 
reach significance in the Hochberg procedure described in Section 8.2.4. This 
approach protects the significance level for each of the doses tested in the final 
analysis.  
An O’Brien-Fleming type Lan-DeMets beta spending function (using beta of 20%) 
will be used to assess futility at the time of the interim analysis. The futility 
boundary will be non-binding and used for information only. 
3.4.2 
Interim Analysis 2 
After the first interim analysis was conducted, it was determined an additional 
interim analysis will be necessary to enable the Sponsor to plan future trials of X82 
in wet AMD or other indications and to determine if 1,2, or all doses should be 
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discontinued. The second interim analysis will be reviewed by the DSMB and by a 
small group of individuals designated by the Sponsor.  
The second interim analysis is planned to be performed once approximately 90% of 
all subjects have reached their week 36 visit. The primary efficacy outcome will be 
tested using the O-Brien-Fleming type Lan-Demets alpha spending function using 
the same approach as described in section 3.4.1. The calculation will take into 
consideration the first interim analysis, i.e. the first information fraction will be 
used in the calculation, along with the second information fraction. This accounts 
for the alpha that was spent at the first interim analysis, thus preserving the 
overall type I error of the entire trial. Since the purpose of this interim analysis is 
to fully explore the data to inform the design of a phase III trial, all endpoints, 
except the fluorescein angiogram endpoints, will be analyzed and a complete set of 
tables and figures will be produced for the interim as well as for the final analysis. 
If one or more of the doses of X82 is stopped for any reason, any hypothesis test 
result from the final analysis regarding those dropped doses will be considered 
exploratory. The Hochberg procedure described in Section 8.2.4 will be applied to 
all 3 doses to preserve the significance level at final analysis for testing of the 
doses not dropped.  
4. 
General Analysis Definitions 
Data will be analyzed using SAS (Version 9.3 or higher) or R version (3.0 or 
higher). Descriptive analyses will be performed on baseline, safety, and efficacy 
data. All tables will be created by treatment arm (X-82 50 mg, X-82 100 mg, X-82 
200 mg, Placebo) and Overall, unless otherwise specified. 
No tests of significance will be carried out to compare treatment arms on baseline 
data because any observed differences between them must be attributed to 
chance. 
Descriptive statistics will be tabulated as follows:  
 
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages. 
 
Continuous data will be summarized using number of non-missing values 
(n), mean, standard deviation, median, minimum and maximum values.  
Listings with individual values will be provided for all data presented in the tables.  
4.1 
Definition of Populations 
4.1.1 
Intention-To-Treat (ITT) Population  
The Intention-To-Treat population (ITT) will consist of all randomized subjects, 
whether or not they receive one dose of study drug. Subjects who receive the 
wrong study medication will be analyzed in the arm to which they were 
randomized. 
The primary, secondary, and other efficacy outcome analyses will be performed on 
the ITT population. This will be considered the main analysis set. 
4.1.2 
 Per Protocol (PP) Population 
The Per Protocol Population will consist of all ITT subjects without any major 
deviation of the protocol. Major deviations are deviations that will likely have a 
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significant impact on the primary analysis of visual acuity. These are considered 
major deviations: 
1. Inclusion/exclusion criteria not met 
2. Receiving an incorrect treatment kit (regardless of the treatment 
contained in the kit) 
3. Missing >=15% of planned X-82 doses for the entire study 
Subjects to be excluded from the Per Protocol Population based on the criteria 
above will be finalized at a pre-analysis meeting before database lock. This process 
is described in a separate document entitled ‘Per Protocol Population Adjudication 
Process’. 
The analyses of primary and secondary efficacy outcomes will be performed on the 
Per Protocol Population as a sensitivity analysis. Demographic information will also 
be provided on the Per Protocol Population.  
4.1.3 
Safety (SAF) Population  
The Safety population will include all subjects who received at least one dose of 
study medication. Subjects will be analyzed according to the treatment arm 
corresponding to the majority of doses they actually received. For example, a 
subject randomized to the 50 mg arm where the majority of doses actually taken 
were 100 mg doses, the subject would be included in the 100 mg arm for safety 
analyses.  
4.2 
Definition of Baseline 
A baseline measurement is defined as the last non-missing measurement taken on 
or before Day -1. 
4.3 
Study Completion 
For the purposes of analysis, a subject will be considered a study completer if the 
subject has completed the Week 52 visit and has not answered “yes” to the 
question, “did the subject prematurely discontinue”. 
 
4.4 
Calculated Variables 
4.4.1 
Study Day 
The day of the first day of X-82 treatment is considered Study Day 1. The day 
before the first day of X-82 treatment is considered Day -1 (there is no Day 0). 
Calculation of Study Day is as follows: 
 
If the event date is ≥ date of first day of X-82 treatment, then Study Day = 
(event date – first day of X-82 treatment + 1) 
 
If the event date is < date of first day of X-82 treatment, then Study Day = 
(event date – first day of X-82 treatment) 
4.4.2 
Duration 
The duration (days) between a start and stop date is calculated as (stop date – 
start date + 1).  
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4.5 
Handling of Unscheduled and Early Withdrawal Visits 
4.5.1 
Visual Acuity Outcome 
For by-visit summary tables of the visual acuity outcome, data from unscheduled 
visits will not be included, and early withdrawal will be considered a separate visit. 
Unscheduled visits will be included in the listing.  
For the efficacy analyses of visual acuity using the model for repeated measures 
and proportion of subjects maintaining vision at week 52 (see Section 8 of this 
SAP), visit windowing will be used to assign unscheduled or early withdrawal visits 
in place of scheduled visits with missing visual acuity. The below table defines the 
windows (low, high) where an unscheduled or early withdrawal visit would be 
mapped to a visit. The process is as follows: 
Consider all visits (scheduled, unscheduled, or early withdrawal) occurring in the 
visit windows defined below. 
 
If a scheduled visit exists with non-missing visual acuity, the data from this 
visit will be used in the analysis.  
 
If visual acuity is missing at a scheduled visit but unscheduled or early 
withdrawal visits occur in the visit window, the data from the visit closest to 
the Study Day Target (including before/after) will be used in the analysis. If 
there are two or more unscheduled or early withdrawal visits both closest 
and equidistant from the Study Day Target, the average of the visual acuity 
values from these visits will be used. 
 
Study Day Target 
Low 
High 
Assigned Visit 
Day 29  
1 
43 
Week 4 
Day 57  
44 
71 
Week 8 
Day 85  
72 
99 
Week 12 
Day 113  
100 
127 
Week 16 
Day 141  
128 
155 
Week 20 
Day 169  
156 
183 
Week 24 
Day 197  
184 
211 
Week 28 
Day 225  
212 
239 
Week 32 
Day 253  
240 
267 
Week 36 
Day 281  
268 
295 
Week 40 
Day 309  
296 
323 
Week 44 
Day 337  
324 
351 
Week 48 
Day 365  
352 
379 
Week 52 
 
4.5.2 
Safety Outcomes 
For by-visit summary tables, data from unscheduled visits will not be included, and 
early withdrawal will be considered a separate visit. There will be no visit 
windowing for unscheduled visits.  
Data from both unscheduled and early withdrawal visits will be considered for 
summaries of the worst post-baseline value.  
 
 
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4.6 
Partial Dates 
Missing or partially missing dates will not be imputed at the data level. However, 
assumptions for missing or partially missing dates for important variables will be 
made to allow inclusion of appropriate data records in the analyses. In general, the 
assumptions about the missing or partially missing dates, when needed, are made 
conservative to avoid overestimation of treatment effects and underestimation of 
adverse effects.  
If a medication date or time is missing or partially missing, so it cannot be 
determined whether it was taken prior or concomitantly, it will be considered both 
as a prior and a concomitant medication. 
If the partial AE onset date information does not indicate whether the AE started 
prior to treatment or after treatment, the AE will be classified as started after 
treatment. 
4.7 
Methods To Be Used For Handling Missing Data 
4.7.1 
Descriptive Analyses 
When summarizing categorical variables, subjects with missing data are generally 
not included in the calculations of percentages unless otherwise specified. When 
needed, the category of “Missing” is created and the number of subjects with 
missing data is presented. 
When summarizing continuous variables, subjects with missing data are not 
included in calculations. No imputations are made.  
4.7.2 
Inferential Analyses 
Methods that take into account the presence of missing data and that yield valid 
estimates under the assumption of data missing at random (MAR) will be used for 
the primary efficacy analysis. In particular, a Model for Repeated Measures fitted 
by Restricted Maximum Likelihood (REML) will be used. Multiple imputation will be 
used in sensitivity analyses of the primary efficacy outcome to impute the missing 
VA data. No imputations will be made for analyses of secondary or other efficacy 
outcomes. 
4.8 
Additional Analyses not Listed in the Protocol 
There may be additional exploratory analyses performed on the FA or OCT data as 
described in section 8.4.3 which are not listed in the protocol.  
5. 
Study Subjects 
5.1 
Disposition of Subjects 
The number of subjects screened, randomized, and treated will be presented. The 
reason for exclusion from one or more analysis sets will be summarized. The 
number of subjects in each of the following randomization strata will also be 
presented: 
1. Previous Treatment Schedule: every 6 weeks or less versus every 8 weeks (includes 
anything more than 6 weeks) 
2. Anti-VEGF received: Eylea, Avastin, Lucentis 
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The frequency of premature discontinuations from the study will be given for the 
ITT population by treatment arm and overall. The primary reason for non-
completion of the study will be summarized.  
The details of the reason for the premature discontinuation (‘Serious Adverse 
Event’, ’Protocol Deviation’, ’Adverse Event’,  ‘Pregnancy’, ’Withdrawal of Consent’, 
’Death’, ’Investigator’s Decision’, ‘Subject Never Took Study Treatment’, ’Other’) 
will be included in a listing. 
5.2 
Protocol Deviations 
All protocol deviations will be assessed and identified prior to database lock to 
determine whether they are major. Subjects with major protocol deviations will be 
excluded from the Per-Protocol Population, as described in section 4.1.2.  
The major protocol deviations will be summarized for the ITT Population. The 
details will be listed by subject and by treatment arm.  
5.3 
Inclusion and Exclusion Criteria 
A frequency table of all inclusion and exclusion criteria not met will be provided for 
the ITT population by treatment arm and overall. A detailed listing will be provided 
by subject.  
5.4 
Out of Window Visits 
Visits that occur out of window according to the schedule of visits in protocol 
Section 9 and appendix 1 will be summarized by visit by dose, overall, and by 
subject. 
5.5 
Re-treatment Criteria Adherence 
A cross tabulation of subjects who received re-treatment with anti-VEGF and who 
met re-treatment criteria in section 6.3 of protocol version 7 will be summarized. A 
listing of discrepancies will be provided by subject. The listing will include 
treatment arm, subject ID, age, sex, race, date of visit (Study Day), visit, anti-
VEGF injection received at visit (Yes/No), re-treatment criteria met (Yes/No), and 
which re-treatment criteria was met (if applicable). This listing will be sorted by 
treatment arm, subject ID, and date of visit. 
5.6 
Food and Alcohol Intake 
The percentages of subjects who report taking study drug with food and without 
alcohol as specified in the protocol section 6.2 will be summarized by visit overall 
and by dose. A listing of alcohol intake will be provided by subject. The listing will 
include treatment arm, subject ID, age, sex, race, date of visit (Study Day), visit, 
and alcohol taken with study drug (Yes/No/Do not recall). This listing will be sorted 
by treatment arm, subject ID, and date of visit. 
6. 
Demographic and other Baseline Characteristics 
Descriptive statistics will be provided to document baseline and on-trial 
comparability, including demographic information and treatment administration.  
Descriptive statistics with respect to subject characteristics at baseline will be 
displayed for the ITT Population. Demographic data will also be provided for the PP 
population.  
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The variables to be summarized are: 
 
Sex, Age, Race, Ethnicity  
 
Prior Ocular History (other than AMD) – Study Eye 
 
Medical History (other than Ocular History) 
 
Wet AMD History – Study Eye 
 
Vital Signs (Height, Weight, Pulse, Blood Pressure) 
 
Pregnancy Test (if done) 
 
Visual Acuity, both eyes 
 
Tonometry, both eyes 
 
ECG 
 
Ophthalmic exam, both eyes 
 
Imaging assessments, study eye 
Prior ocular history (other than AMD) and medical history terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) version 18.0. Subjects 
will only appear in the table once per System Organ Class (SOC) or Preferred Term 
(PT), although they may have experienced multiple events. Summary tables will be 
sorted alphabetically by SOC then by PT within SOC based on descending 
frequency in the Overall column.  
A summary table will be created for Wet AMD History in the study eye and will 
contain the following information:  
 
Eye affected by Wet AMD (OS/OD) 
 
Time since diagnosis of Wet AMD (months), defined as (Date of 
Randomization – Date of diagnosis)/30.4375 
 
Prior Treatment for Wet AMD (Yes/No). If yes, number and percentage of 
subjects receiving Lucentis/ Avastin/ Macugen/ Eylea/ Other 
The following listings will be created for demographics and other baseline 
characteristics:  
 
Demographics: treatment arm, subject ID, age, sex, race, and ethnicity. 
This listing will be sorted by treatment arm and subject ID. 
 
Prior Ocular History (other than AMD) – Both Eyes: treatment arm, subject 
ID, age sex, race, eye (OS, OD, OU), SOC, PT, reported term, start date, 
stop date, and concomitant treatment (Yes/No). This listing will be sorted by 
treatment arm, subject ID, start date, and reported term. 
 
Medical History (other than Ocular History): treatment arm, subject ID, age, 
sex, race, SOC, PT, reported term, start date, and stop date. This listing will 
be sorted by treatment arm, subject ID, start date, and reported term.  
 
Wet AMD History: treatment arm, subject ID, age, sex, race, eye (OS, OD, 
OU), affected by Wet AMD (Yes/No), date of diagnosis, prior treatment for 
AMD (Lucentis/ Avastin/ Macugen/ Eylea/ Other, specify), and number of 
injections. This listing will be sorted by treatment arm, subject ID, eye, prior 
treatment for AMD.  
Baseline information for other safety and efficacy parameters are presented in 
listings as described in later sections of this SAP. 
 
 
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7. 
Prior and Concomitant Treatment 
Prior treatments are defined as treatments which start or stop prior to the first 
dose of study drug. Concomitant treatments are defined as treatments which start 
or stop after the first dose of study drug. Treatments can be both prior and 
concomitant. If a strict determination can not be made due to missing date or 
month, the treatment may be considered both prior and concomitant. 
7.1 
Prior and Concomitant Medications 
All prior and concomitant medications will be summarized separately by WHO Drug 
Code (Version 3 2014) on the ITT Population. Medication usage will be summarized 
according to the 1st level and the 4th level Anatomic Therapeutic Chemical (ATC) 
classification.  
Subjects will only be included once in the respective summaries for any ATC level 1 
(ATC1) or any ATC level 4 (ATC4) classification. The summary tables will be sorted 
alphabetically by ATC1 then by ATC4 within ATC1 based on descending frequency 
within the Overall column.  
Prior and concomitant medications will be presented in a listing. This listing will 
display treatment arm, subject ID, age, sex, race, ATC1, ATC4, medication name, 
start date (Study Day of Start), stop date (Study Day of Stop), prior/concomitant 
(P/C), associated eye (OD, OS, OU), indication, and given to treat AE (Yes/No). 
This listing will be sorted by treatment arm, subject ID, start date, and reported 
term.  
7.2 
Prior and Concomitant Surgeries/Procedures 
Prior and Concomitant surgeries/procedures will be coded using the same version 
of MedDRA as for Medical History. Summary tables will present prior and 
concomitant surgeries/procedures by SOC and PT for the ITT Population. Subjects 
will only be included in each summary once per SOC or PT. Each summary will be 
sorted alphabetically by SOC then by PT within SOC based on descending 
frequency within the Overall column.  
A listing of all surgeries/procedures will be created. This listing will display 
treatment 
arm, 
subject 
ID, 
age, 
sex, 
race, 
SOC, 
PT, 
reported 
term, 
surgery/procedure date (Study Day), prior/concomitant (P/C), indication, and given 
to treat AE (Yes/No). The listing will be sorted by treatment arm, subject ID, 
surgery/procedure date, and reported term.  
8. 
Efficacy Evaluation  
Efficacy analyses will be conducted for the ITT Population and the primary and 
secondary efficacy outcome analyses will be repeated using the PP Population. The 
primary analysis will be based on a Model for Repeated Measures (MRM). This 
analysis provides valid estimates as long as the missing data mechanism fulfills the 
Missing at Random (MAR) assumption. No imputation will be done for the primary 
analysis.  
Sensitivity analyses may be performed to assess the potential magnitude and 
direction of the impact of missing data.   
Unless otherwise stated, summary tables will have columns for each treatment arm 
and an Overall column. 
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8.1 
Control of Type I Error 
The overall level of significance for the primary efficacy analysis is set at 5% (one-
sided).  
For the primary efficacy evaluation, a Hochberg adjustment will be used for the 
pairwise comparisons of each X-82 treatment arm with placebo at the 2 interim 
and final analyses, tested at an  determined by the O’Brien-Fleming type Lan-
DeMets alpha spending function, where the information fractions will be the 
percentage of patients that have completed their 52 week visit. If one or more of 
the doses of X82 is stopped for any reason after the second interim analysis, any 
hypothesis test result from the final analysis regarding those dropped doses will be 
considered exploratory. The Hochberg procedure described in Section 8.2.4 will be 
applied to all 3 doses to preserve the significance level at final analysis for testing 
of the doses not dropped. 
8.2 
Analysis of Primary Efficacy Outcome 
8.2.1 
Best Corrected Visual Acuity (BCVA)  
The Best Corrected Visual Acuity (BCVA) will be determined for each subject in 
each eye at each visit. The BCVA in the study eye will be used for the analyses. 
Details of the procedure are in Appendix 7 of the Study Protocol. The BCVA is 
calculated as follows:  
 
If 20 or more ETDRS letters are read correctly at 4 meters, the BCVA is 
calculated as that number of letters plus 30.  
 
If fewer than 20 ETDRS letters are read correctly at 4 meters, the BCVA is 
calculated as the number of letters read correctly at 1 meter plus the 
number, if any, read at 4 meters.  
 
If no letters are read correctly at either 4 meters or 1 meter, the BCVA 
score is recorded as 0.  
8.2.2 
MRM Model 
The mean change in visual acuity (ETDRS BCVA) in each of the X-82 arms will be 
compared to the mean change in VA in the placebo arm from Day -1 up to and 
including the Week 52 visit for the study eye. A restricted maximum likelihood 
(REML)-based repeated measures approach will be used [Mallinckrodt,2008].  
Data from all scheduled post-baseline visits up to and including the outcome visit 
(52 weeks) will be used in the analysis. The repeated measures model will include 
the fixed, categorical effects of treatment and visit and the treatment-by-visit 
interaction; the continuous, fixed covariate of baseline visual acuity score; the 
fixed, categorical effect of type of anti-VEGF received (Eylea, Avastin, Lucentis); 
and the baseline score-by-visit interaction.  
The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The 3 pair-wise comparisons will be the tests for the treatment effect at 
the endpoint visit (52 weeks) obtained by using an appropriate contrast of the 
treatment-related model parameters. See Section 8.2.3 for testing details. 
 
 
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Pseudo code: 
proc mixed data=VAdata method=reml; 
 class usubjid trtn injtype visit; 
 model vas_dif= visit trtn baseva injtype trtn*visit baseva*visit / 
ddfm=kenwardroger solution; 
 repeated visit / type= UN subject=usubjid; 
lsestimate trtn*visit “Placebo - Dose 1 at Week 52” [1,1 13] [-1,2 13] 
/lower testvalue=9 alpha=0.05 CL;    
lsestimate trtn*visit “Placebo – Dose 2 at Week 52” [1,1 13] [-1,3 13] 
/lower testvalue=9 alpha=0.05 CL;    
lsestimate trtn*visit “Placebo – Dose 3 at Week 52” [1,1 13] [-1,4 13] 
/lower testvalue=9 alpha=0.05 CL;    
run; 
Where  
trtn= treatment assignment 
Baseva= baseline VAS (continuous) 
Injtype= injection type  
 
8.2.3 
Variance-Covariance Structure 
An unstructured covariance matrix will first be used to model the within-subject 
errors, allowing flexibility in the variance and correlation estimates. If there are 
convergence problems in fitting the model, a heterogeneous Toeplitz covariance 
matrix will be used. This structure allows the correlation between observations to 
vary depending on the position of the observation in the longitudinal sequence. For 
example, the correlations between adjacent observations are assumed to be 
identical but are allowed to differ from the correlation between observations that 
are two positions apart in the sequence.  
If there are still convergence problems, a first-order heterogeneous autoregressive 
structure will be considered in order to simplify the variance-covariance structure. 
This structure does allow the correlation between observations to depend on the 
position of the observations in the longitudinal sequence. However, it is less flexible 
than the heterogeneous Toeplitz structure because it assumes that the correlation 
is a function of the distance between observations, with observations measured 
further apart being less correlated.  
If convergence problems remain, an autoregressive structure of order 1 will be 
considered as the final candidate. This structure allows the correlation between 
observations to depend on the position of those observations in the longitudinal 
sequence. However, it assumes that the correlation is a function of a single 
parameter. 
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8.2.4 
Testing Procedure 
The Hochberg procedure will be followed for testing the non-inferiority of the three 
doses versus placebo for both the interim and final analyses. The individual null 
hypotheses are that the doses are inferior to placebo by at least 9 letters. The 
overall alpha level for the testing procedure will be calculated at the 2 interim and 
final analyses using an alpha spending function to control for the type I error of 
0.05.  
Let θ1, θ2, and θ3 represent the pairwise differences of each dose of X-82 with 
placebo in mean changes from baseline in VA at 52 weeks (placebo-treatment). 
Assume, without loss of generality, p1, p2, and p3 are the unadjusted p-values from 
individual tests of H0i: θi >= 9, i=1,2,3 and assume p1≥p2≥p3. Let  be the 
significance level appropriate for the analysis (interim or final), provided by the 
O’Brien-Fleming type Lan-DeMets alpha spending function, given the information 
fraction at the time of the analysis. 
If p1<, then the conclusion is that all three doses are non-inferior to placebo and 
the choice of dose must be based on other considerations.  
Otherwise, testing will proceed as follows: If p1≥ and p2</2, the doses 
corresponding to p2 and p3 are non-inferior to placebo. If p1≥ and p2≥/2 and 
p3</3, the dose corresponding to p3 is non-inferior to placebo. If p1≥ and p2≥/2 
and p3≥/3, no dose can be declared non-inferior to placebo. 
8.2.5 
Data Displays 
A summary table will present summary statistics for VA at baseline and 52 weeks 
as well as the change from baseline at 52 weeks. Inferential statistics from the 
MRM model (difference in least squares means, standard error, Wald test statistic, 
p-value, and 95% asymptotic confidence interval) will be presented for the 
pairwise comparisons of each dose of X-82 with placebo. These will be obtained via 
appropriate contrasts in the MRM model. 
A separate summary table will present summary statistics by treatment arm and 
by visit for VA and the change from baseline.  
Plots of the mean VA over time will be created with overlay by treatment arm.  
A listing will display the VA for each subject at each time point. This listing will 
include treatment arm, subject ID, age, sex, race, date of assessment, visit, and 
VA result. This listing will be sorted by treatment arm, subject ID, and date of 
assessment.  
8.3 
Analysis of Secondary Efficacy Outcome 
A summary table will be created which will display summary statistics in each 
treatment arm for the number of anti-VEGF injections received (normalized for the 
number of months on study) during the first 52 weeks after randomization. The 
normalization will be calculated as  
(number of anti-VEGF injections received)*12/(time on study in months) 
Where the time on study (months) = (date of study completion/early 
discontinuation – date of randomization + 1)/30.4375.  
A separate summary table will be created which will display the summary statistics 
in each treatment arm for the number of anti-VEGF injections received during the 
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first 52 weeks after randomization, in the subset of subjects who completed the 
study (see Section 4.3).  
In addition, the secondary efficacy outcome (number of injections per year) will be 
tested for any dose reaching significance for the primary outcome (visual acuity) at 
the time of final analysis. A two-way analysis of variance will be performed with 
treatment arm and type of anti-VEGF (Eylea, Avastin, Lucentis) as categorical 
grouping variables and will be adjusted for previous treatment schedule as entered 
into the IWRS at the time of randomization (every 6 weeks or less versus every 8 
weeks). Pairwise comparisons of X-82 dose groups with placebo will be conducted. 
The tests will use the same significance level for the secondary efficacy outcome as 
for the primary outcome (e.g. if =0.04 at the final analysis for the primary 
efficacy outcome, the secondary efficacy outcome will be tested at =0.04) and will 
use the Hochberg procedure. The normal distribution assumption will be checked 
by visual inspection of histograms of the distribution of the number of anti-VEGF 
injections within each treatment arm.  
8.4 
Analysis of Other Efficacy Outcomes 
8.4.1 
Analysis of Maintaining Vision at Week 52 
Proportion of subjects maintaining vision at week 52 (loss of less than 15 letters 
from Day -1) will be summarized descriptively and any inferential analyses will be 
considered exploratory.  
8.4.2 
Imaging-Based Outcomes 
Summary statistics for the following fluorescein angiogram endpoints in the study 
eye and fellow eye (of all subjects and of subjects with unilateral disease) will be 
presented by treatment arm and overall. The values at screening visit 2 and 52 
weeks, as well as the change from screening visit 2 at 52 weeks will be presented 
for: 
 
Observed Classic, Occult, and Total CNV area (mm2)  
 
Observed total lesion size (mm2)  
 
Observed area of fibrosis (mm2)  
 
Observed area of hemorrhage (mm2)  
Summary statistics for the following SD-OCT endpoints in the study eye and fellow 
eye (of all subjects and of subjects with unilateral disease) will be presented by 
treatment arm and overall. The values at screening visit 2 and 52 weeks as well as 
the change from screening visit 2 at 52 weeks will be presented for: 
Main outcomes 
 
Observed central retinal lesion thickness (µm)  
 
Observed central subfield thickness (µm)  
 
Observed macular volume (mm3)  
Additional outcomes 
 
Observed greatest subretinal fluid height (µm)  
 
Presence of subretinal fluid(yes or no)  
 
Observed height of the RPE elevation (PED) (µm)  
 
Presence of inter-retinal cysts(yes or no)  
 
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Continuous imaging-based measurements by multiple readers will be averaged.  
Separate listings will be produced for the FA and SD-OCT parameters. The listings 
will include treatment group, subject identifier, visit date (Study Day), visit, 
parameter, units, and result. The listings will be sorted by treatment group, subject 
identifier, and visit date.  
8.4.3 
Supportive Analysis of Time to First anti-VEGF Injection 
The time from Day 1 to first anti-VEGF injection will be analyzed as a time-to-event 
variable using Kaplan-Meier methods. For subjects who receive an anti-VEGF 
injection after Day 1, the time to first injection (in Weeks) will be calculated as 
(Date of first anti-VEGF injection after Day 1 - Date of Day 1 + 1)/7. Otherwise, 
subjects who do not have an anti-VEGF injection after Day 1 will be censored at the 
date of their last visit. The Kaplan-Meier curves will be plotted for each treatment 
arm. Additionally, the median time to first anti-VEGF injection will be calculated for 
each treatment arm and displayed on the plot.  
8.4.4 
Analyses in Fellow Eye  
It is of interest to examine how study drug affects the non-affected fellow 
eye.  Analysis of the endpoints listed below will be conducted in the fellow eye. 
Endpoints will be summarized descriptively, and any inferential analyses will be 
considered exploratory:  
The following analysis will be done only in subjects with unilateral disease. 
Subjects with unilateral disease are those with Wet AMD diagnosed only in the 
study eye at baseline: 
 
Conversion of Fellow Eye  
Proportion of subjects developing bilateral AMD by 52 Weeks will be 
summarized descriptively. The development of Wet AMD in the fellow eye 
will be captured as an adverse event with MedDRA preferred 
term(AEDECOD) of ‘Neovascular age-related macular degeneration’. 
 
The following analyses will be done in all subjects as well as subjects with 
unilateral disease: 
 
Mean change in Visual Acuity  
Mean change in visual acuity from Day -1 to Week 52 will be analyzed 
using the repeated measures model described in section 8.2.2.  
 
Number of Injections per Year  
Mean number of injections per year will be analyzed using the approach 
described in 8.3. 
8.5 
Sensitivity Analyses 
The primary and secondary efficacy analyses will be repeated on the PP Population. 
For the primary efficacy analysis, multiple imputation may be applied to assess the 
impact of missing data. A model compatible with the following Missing Not At 
Random (MNAR) missingness mechanism ‘pattern-mixture-model imputation’ will 
be implemented (using SAS PROC MI). The missing values at a particular visit will 
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be imputed by using the pattern-mixture-model restrictions. In particular, 
Neighboring-Case Missing Value (NCMV) restrictions will be applied.  
This approach can be applied to data with monotone missing data patterns. Hence, 
if necessary to apply the approach, the data will be transformed into the monotone 
patterns by considering the longest uninterrupted sequences of the measurements 
for the subjects and/or excluding a few measurement visits from modelling, to 
increase the number of monotone patterns in the data. In case data are re-shaped, 
the primary analysis MRM model will be applied to the re-shaped data as well.  
No data imputations will be performed on the secondary efficacy analyses or other 
efficacy analyses.  
9. 
Safety Evaluation 
All safety analyses will be performed on the Safety Population. The analyses will be 
conducted according to the treatment that subjects actually received. Missing 
values of safety data will not be imputed, and safety summaries will be based on 
the observed cases. All safety summaries will be descriptive; there will be no 
inferential statistics produced for any safety endpoints. 
All Safety summary tables will be presented by treatment arm and overall, unless 
otherwise specified.  
9.1 
Extent of Exposure 
9.1.1 
Exposure to X-82 
A summary table of exposure to study drug will be created and will contain the 
following information: 
 
Frequency and percentage of subjects receiving all study drug 
1. If No, summary statistics of total number of days dose of study drug 
interrupted 
2. If No, frequency and percentage of subjects with reason for interruption of 
study drug (‘Took only one of the two pills’, ‘Forgot to take the two pills’, 
‘SAE/AE’, ‘Took four pills’). Note: A subject may have more than one 
reason for dose interruption of study drug 
A dose interruption is defined by at least one or more days where a subject 
deviated from the planned dose.   
 
A listing of exposure to study treatment will be created. The listing will include 
treatment arm, subject ID, age, sex, race, date of visit (Study Day), visit, anti-
VEGF injection received at visit (Yes/No), did subject take all X-82 since last visit 
(Yes/No), number of days X-82 dose interrupted, and reason for X-82 dose 
interruption. This listing will be sorted by treatment arm, subject ID, and date of 
visit.  
For all treatment arms, including placebo, a summary table of number of missed 
doses by subject by visit and for the entire 52-week period will be created. In 
addition, number of missed doses by visit and for the entire 52-week period per 
treatment group will be presented in a summary table for the ITT population. For 
subjects that terminate early, any doses after early termination will not be counted 
as missed.  
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9.1.2 
Exposure to anti-VEGF Treatment 
A summary table of exposure to anti-VEGF treatments will be created and will 
contain the following information: 
 
Frequency and percentage of subjects receiving anti-VEGF injection at 
Screening Visit 1 by type (Eylea, Avastin, Lucentis) 
 
Frequency and percentage of subjects receiving anti-VEGF injection on Day 
-1 by type (Eylea, Avastin, Lucentis) 
 
Summary statistics of number of Eylea injections received 
 
Summary statistics of number of Avastin injections received 
 
Summary statistics of number of Lucentis injections received 
A listing of anti-VEGF exposure will be created. The listing will include treatment 
arm, subject ID, age, sex, race, date of visit (Study Day), visit, and anti-VEGF 
injection received (Eylea, Avastin, Lucentis). This listing will be sorted by treatment 
arm, subject ID, and date of visit.  
9.2 
Adverse Events 
Adverse events which begin on or after Day 1 (day of the first planned dose of 
study drug) or up to and including 30 days after the last dose of study drug will be 
considered treatment-emergent adverse events (TEAEs). All adverse events will be 
coded using MedDRA version 17.1.  
For TEAEs related to X-82, the possible option as entered in the eCRF is ‘Related’. 
Refer to the Clinical Trial Protocol for specific definitions.  Adverse events where 
the relationship to study drug is unknown will be classified as ‘Related’. Related 
adverse events will further be classified by the Sponsor as ‘Expected’ or 
‘Unexpected’ based on the definitions in the Study Protocol.  
Ophthalmic TEAEs are those TEAEs which have a SOC of ‘Eye Disorders’, or SOC of 
‘Investigations’ with PT ‘Intraocular pressure increased’.  
Cardiovascular events of interest(EOI) are those considered as acquired, non-
traumatic heart or blood vessel diagnoses. Cardiovascular EOI are TEAEs which 
satisfy one of the following conditions: 
1. 
SOC "Cardiac disorders", without high level group term (HLGT) 
"Congenital cardiac disorders" 
2. 
SOC "Vascular disorders", without HLGT "Lymphatic vessel 
disorders", without HLGT "Vascular injuries" 
3. 
SOC "Eye disorders", with only HLGT "Ocular haemorrhages and 
vascular disorders NEC" 
4. 
SOC "Nervous system disorders", with only HLGT "Central nervous 
system vascular disorders", without high level term (HLT) 
"Traumatic central nervous system haemorrhages" 
Summary tables will include only TEAEs, and listings will include all adverse events 
reported in the clinical database.  
 
The following summaries of TEAEs will be provided: 
 
Overall summary of TEAEs (including number of subjects with at least one 
TEAE, number of subjects with at least one related TEAE, number of 
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subjects with at least one serious TEAE, number of subjects with at least 
one related serious TEAE, number of subjects with at least one severe TEAE, 
number of subjects with a TEAE leading to discontinuation, and number of 
subjects with a TEAE leading to death) 
 
TEAEs by SOC and PT 
 
Related TEAEs by SOC and PT 
 
Expected TEAEs by SOC and PT 
 
TEAEs by SOC, PT, and Severity 
 
Related TEAEs by SOC, PT, and Severity 
 
Ophthalmic TEAEs in Study Eye by PT 
 
Related Ophthalmic TEAEs in Study Eye by PT 
 
Ophthalmic TEAEs in Fellow Eye by PT 
 
Related Ophthalmic TEAEs in Fellow Eye by PT 
 
Cardiovascular Events of Interest by PT and Severity 
 
TEAEs leading to permanent discontinuation of study drug 
 
Related TEAEs leading to permanent discontinuation of study drug 
 
TEAEs leading to death 
 
Related TEAEs leading to death 
For summaries by SOC and PT, a subject will only be counted once for each PT and 
once for the overall count for a SOC. However, subjects may be included in more 
than one PT category within a SOC. For summaries which also include severity, a 
subject who experiences the same event more than once will have the event with 
the worst severity counted in the summary. Summaries by SOC and PT will be 
presented alphabetically within SOC then by descending frequency of PT within 
SOC based on the overall column. 
In addition to tabular summaries, listings will be created as follows: 
 
Overall listing of AEs containing treatment arm, subject ID, age, sex, race, 
SOC, PT, reported term, start date (Study Day of Start), stop date (Study 
Day of Stop), duration, TEAE (Y/N), serious (Y/N), associated eye 
(OD/OS/OU), severity (Mild/Moderate/Severe), relationship (Related/Not 
Related), outcome, action taken.  
 
Listing of Cardiovasular AEs will contain the same information as the Overall 
AE listing (the listing will only include AEs identified as Cardiovascular AEs) 
 
Listing of AEs leading to permanent discontinuation will contain the same 
information as the overall listing of AEs except for action taken (the listing 
will only include AEs with action = drug withdrawn). 
 
Listing of AEs leading to death will contain the same information as the 
overall listing of AEs except for outcome (the listing will only include AEs 
with outcome = fatal).  
The adverse event listings will be sorted by treatment arm, subject ID, start date, 
and reported term.  
9.3 
Deaths and Serious Adverse Events  
Serious adverse events (SAEs) will be summarized grouped by SOC and PT. Deaths 
will be summarized in a separate table which will include tabulations of the number 
of subjects who died as well as the reason for death.  
 
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In addition to tabular summaries, the following listings will be created: 
 
Listing of serious adverse events will be created by treatment arm including 
the treatment arm, subject ID, age, sex, race, SOC, PT, reported term, start 
date (Study Day of Start), stop date (Study Day of Stop), duration, TEAE 
(Y/N), associated eye (OD/OS/OU), severity (Mild/Moderate/Severe), 
relationship (Related/Not Related), outcome, action taken. 
 
Listing of deaths will be created which will include treatment arm, subject 
ID, age, sex, race, death date, reason for death, details (as provided in 
eCRF).  
The SAE listing will be sorted by treatment arm, subject ID, start date, and 
reported term. The death listing will be sorted by treatment arm and subject ID. 
9.4 
Clinical Laboratory Determination 
Clinical laboratory parameters will be graded (as applicable) using the National 
Cancer Institute’s Common Terminology Criteria (NCI-CTC) version 4.03. 
Laboratory parameters which cannot be graded will be given the designation of 
‘Normal’ or ‘Abnormal’, where ‘Abnormal’ is defined as outside of the range of [LLN, 
ULN].  
Parameters to be summarized are as follows:  
 
Hematology: White Blood Cells, Absolute Neutrophil Count, Absolute 
Basophil Count, Absolute Eosinophil Count, Absolute Lymphocyte Count, 
Hematocrit, Hemoglobin, Platelets, Mean Corpuscular Volume (MCV), Mean 
Corpuscular 
Hemoglobin 
(MCH), 
Mean 
Corpuscular 
Hemoglobin 
Concentration (MCHC) 
 
Biochemistry: Blood Glucose, Blood Urea Nitrogen, Creatinine, Sodium, 
Potassium, Magnesium, Chloride, Calcium, Phosphate, Carbon Dioxide, 
Alkaline Phosphatase, AST (SGOT), ALT (SGPT), Total Bilirubin, Total 
Protein, Albumin, Estimated Glomerular Filtration Rate (using the CKD-EPI 
equation) 
 
Coagulation: PT, PTT, INR 
 
Thyroid Function: Serum TSH, total T3, free T4 
 
Additional Serum: Lipase, Amylase, Creatinine Kinase 
 
Urinalysis: pH, Specific Gravity, Microscopic Examination 
For continuous laboratory parameters, summaries of the values and changes from 
baseline will be presented for each visit by parameter. Plots of mean changes in 
laboratory values over time will be presented by dose group separately for the 
following parameters: ALT, AST, WBC, Absolute Neutrophil Count, Absolute 
Lymphocyte Count, Platelets, TSH, Free T4, Total T3.  
For categorical laboratory parameters, the frequencies and percentages of subjects 
in each category at each visit will be presented by parameter. 
Where applicable, the shift from baseline NCI-CTC grade to worst post-baseline 
NCI-CTC grade will be presented for each parameter. This summary will include all 
scheduled and unscheduled post-baseline visits in the derivation of worst post-
baseline grade.  
For parameters without NCI-CTC grading, the shift from baseline abnormality 
categorization 
(‘Normal’,’Abnormal’) 
to 
worst 
post-baseline 
abnormality 
categorization (‘Normal’,’Abnormal’) will be presented for each parameter. This 
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summary will include all scheduled and unscheduled post-baseline visits in the 
derivation of the worst post-baseline abnormality categorization.   
A listing of clinical laboratory values will be created. This listing will include 
treatment arm, subject ID, age, sex, race, laboratory category, laboratory 
parameter, date of collection (Study Day), visit, result, units, LLN, ULN, NCI-CTC 
Grade (if applicable). Values to be considered abnormal (<LLN or >ULN) will be 
flagged in the listing. This listing will be sorted by treatment arm, subject ID, 
laboratory category, laboratory parameter, and date of collection. 
9.5 
Vital Signs, Physical Findings and Other Observations Related to 
Safety 
9.5.1 
Vital Signs 
A summary table will be created to display the values and changes from baseline 
for vital sign parameters by visit. The vital sign parameters to be summarized are 
Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse Rate 
(beats/min), Weight (kg), and Height (cm). Height will only be summarized at 
baseline.  
A listing of vital signs will also be presented. This listing will display treatment arm, 
subject ID, age, sex, race, vital sign parameter (units), date of visit (Study Day), 
visit, results. This listing will be sorted by treatment arm, subject ID, vital sign 
parameter, and date of visit. Vitals signs which are outside of the following 
reference ranges will be flagged on the individual subject data listings:  systolic 
blood pressure (100-150 mmHg), diastolic blood pressure (45-90 mmHg), heart 
rate (50-100 beats per minute [bpm]), body temperature (35.0°C-37.5°C), and 
respiratory rate (8-20 breaths/min). 
9.5.2 
Ophthalmic Examination 
A by-visit summary table will be created to display the frequencies and 
percentages of subjects who have a lens status of ‘Aphakic’, ‘Pseudo-phakic’, or 
‘Phakic’ for the study eye. For those subjects with lens status of ‘Phakic’ at a visit, 
the frequency and percentage of subjects with <1, 1.0, 1.5, 2.0, 2.5, 3.0, and >3 
will be summarized separately for Nuclear, PSC, and Cortical categories.  
A listing will be created to display the results of the ophthalmic examinations at all 
visits. This listing will display treatment arm, subject ID, age, sex, race, date of 
examination (Study Day), visit, OS Lens status (Nuclear, PSC, and Cortical, if 
phakic), and OD Lens status (Nuclear, PSC, and Cortical, if phakic). This listing will 
be sorted by treatment arm, subject ID, and date of examination. 
9.5.3 
Tonometry 
A summary table will be created to display the values and changes from baseline 
for intraocular pressure (IOP) in the study eye by visit.  
A listing will be created to display the IOP values at each visit. This listing will 
display treatment arm, subject ID, age, sex, race, date of visit (Study Day), visit, 
IOP value (OS), IOP value (OD), and IOP method. This listing will be sorted by 
treatment arm, subject ID, and date of visit. 
 
 
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9.5.4 
ECG 
A summary table will be created to display ECG results at baseline and at post-
baseline visits. The frequencies and percentages of subjects in the ‘Normal’, 
‘Abnormal, Not Clinically Significant’, ‘Abnormal, Clinically Significant’, ‘Not Done’ 
categories will be displayed.  
A separate table will summarize values and changes from baseline in the ECG 
parameters at each visit. The parameters included will be Ventricular Heart Rate 
(beats/min), PR Interval (msec), RR Interval (msec), QRS Interval (msec), QT 
Interval (msec), and QTcF Interval (msec). QTcF (Fridericia’s correction) is 
calculated as 𝑄𝑇/√𝑅𝑅
3
, where QT is the QT interval measured in milliseconds, and 
RR is the RR interval measured in seconds. 
A by-visit summary table will also be created to display the number and percentage 
of subjects who meet the following criteria: 
 
Increase in QTcF > 30 msec from baseline 
 
Increase in QTcF > 60 msec from baseline 
Subjects who meet the criteria of Increase in > 60 msec will also be included in the 
count of subjects who meet the criteria of Increase in > 30 msec.  
A listing will be created to display the parameter values and results from ECGs 
taken at all visits. The listing will display treatment arm, subject ID, age, sex, race, 
date of visit (Study Day), visit, time, Ventricular Heart Rate (beats/min), PR 
Interval (msec), RR Interval (msec), QRS Interval (msec), QT Interval (msec), and 
QTcF Interval (msec). This listing will be sorted by treatment arm, subject ID, ECG 
parameter, and date of visit. Values outside the following reference ranges will be 
flagged as low (L) or high (H) in the listing: Ventricular Heart Rate (45-90 
beats/min); PR interval (111-209 msec), RR interval (667-1330 msec), QRS 
interval (<121 msec), QT interval (<481 msec), QTcF interval (<431 msec). 
10. References 
1. Busbee BG, Ho AC, Brown DM, Heier JS, Suner IJ, Li Z, Rubio R, Lai P. Twelve-Month 
Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal 
Neovascular Age-related Macular Degenration. Ophthalmology. Mar 2013. Volume 
120, Number 5 
2. DeMets DL, Lan KK, 1994, Interim analysis: The alpha spending function 
approach, Statistics in Medicine 13: 1341-1352. 
3. Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Drug 
Information Journal, 2008. 42:303-319. 
 
 
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11. List of Tables/Graphs/Listings 
11.1 
List of Statistical Tables 
 
Table Number 
Title 
14.1.1.1 
Subject Disposition – All Screened Subjects 
14.1.1.2 
Subject Disposition by Randomization Strata – All Randomization 
Subjects 
14.1.2.1 
Protocol Deviations – ITT Population 
14.1.2.2 
All Inclusion and Exclusion Criteria Not Met – ITT Population 
14.1.2.3 
Out of Window Visits by visit overall and dose group-ITT 
Population 
14.1.2.4 
Out of Window Visits by subject 
14.1.2.5 
Re-treatment Criteria Adherence by Visit 
14.1.3.1 
Demographics and Baseline Characteristics – ITT Population 
14.1.3.2 
Demographics and Baseline Characteristics – PP Population 
14.1.4.1 
Summary of Prior Ocular History by System Organ Class and 
Preferred Term – ITT Population 
14.1.4.2 
Summary of Prior Ocular History by System Organ Class and 
Preferred Term – PP Population 
14.1.4.3 
Summary of Medical History (Excluding Ocular History) by 
System Organ Class and Preferred Term – ITT Population 
14.1.4.4 
Summary of Wet AMD History – Study Eye – ITT Population 
14.1.4.5 
Summary of Wet AMD History – Study Eye – PP Population 
14.1.4.6 
Baseline Ophthalmic Examination Information – ITT Population 
14.1.4.7 
Baseline Ophthalmic Examination Information – PP Population 
14.1.5.1 
Prior Medication [1] – Summary by ATC Code 1 and ATC Code 4 
[2] – ITT Population 
14.1.5.2 
Concomitant Medication [1] – Summary by ATC Code 1 and ATC 
Code 4 [2] – ITT Population 
14.1.5.3 
Summary of Prior Surgeries/Procedures by System Organ Class 
and Preferred Term – ITT Population 
14.1.5.4 
Summary of Concomitant Surgeries/Procedures by System 
Organ Class and Preferred Term – ITT Population 
14.2.1.1 
Mean Change from Baseline in VA at 52 weeks (Primary Efficacy) 
- Study Eye – ITT Population 
14.2.1.2 
Mean Change from Baseline in VA at 52 weeks  - Study Eye - PP 
Population 
14.2.1.3 
Mean Change from Baseline in VA at 52 weeks – Study Eye - 
Multiple Imputation 
14.2.2.1 
Values and Mean Change from Baseline in VA by Visit – Study 
Eye - ITT Population 
14.2.2.2 
Values and Mean Change from Baseline in VA by Visit – Study 
Eye - PP Population 
14.2.3.1 
Anti-VEGF 
Injections 
received 
through 
52 
weeks 
after 
randomization – Study Eye – ITT Population 
14.2.3.2 
Anti-VEGF 
Injections 
received 
through 
52 
weeks 
after 
randomization – Study Eye – PP Population 
14.2.3.3 
Anti-VEGF 
Injections 
received 
through 
52 
weeks 
after 
randomization in Subjects who Completed the Study – Study 
Eye - ITT Population 
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14.2.4.1 
Proportion of Subjects Maintaining Vision within 15 letters- ITT 
Population 
14.2.5.1 
Values and Mean Change from Screening Visit 2 in CNV area 
(mm2) at 52 weeks – Study Eye - ITT Population 
14.2.5.2 
Values and Mean Change from Screening Visit 2 in CNV area 
(mm2) at 52 weeks – Fellow Eye - ITT Population 
14.2.5.3 
Values and Mean Change from Screening Visit 2 in CNV area 
(mm2) at 52 weeks in Subject with Unilateral Disease – Fellow 
Eye - ITT Population 
14.2.6.1 
Values and Mean Change from Screening Visit 2 in Total Lesion 
Size (mm2) at 52 weeks – Study Eye - ITT Population 
14.2.6.2 
Values and Mean Change from Screening Visit 2 in Total Lesion 
Size (mm2) at 52 weeks – Fellow Eye - ITT Population 
14.2.6.3 
Values and Mean Change from Screening Visit 2 in Total Lesion 
Size (mm2) at 52 weeks in Subjects with Unilateral Disease – 
Fellow Eye - ITT Population 
14.2.7.1 
Values and Mean Change from Screening Visit 2 in Area of 
Fibrosis (mm2) at 52 weeks – Study Eye - ITT Population 
14.2.7.2 
Values and Mean Change from Screening Visit 2 in Area of 
Fibrosis (mm2) at 52 weeks – Fellow Eye - ITT Population 
14.2.7.3 
Values and Mean Change from Screening Visit 2 in Area of 
Fibrosis (mm2) at 52 weeks in Subjects with Unilateral Disease – 
Fellow Eye - ITT Population 
14.2.8.1 
Values and Mean Change from Screening Visit 2 in Area of 
Hemorrhage (mm2) at 52 weeks – Study Eye - ITT Population 
14.2.8.2 
Values and Mean Change from Screening Visit 2 in Area of 
Hemorrhage (mm2) at 52 weeks – Fellow Eye - ITT Population 
14.2.8.3 
Values and Mean Change from Screening Visit 2 in Area of 
Hemorrhage (mm2) at 52 weeks in Subjects with Unilateral 
Disease – Fellow Eye - ITT Population 
14.2.9.1 
Values and Mean Change from Screening Visit 2 in Central 
Retinal Lesion Thickness (µm) at 52 weeks– Study Eye - ITT 
Population 
14.2.9.2 
Values and Mean Change from Screening Visit 2 in Central 
Retinal Lesion Thickness (µm) at 52 weeks– Fellow Eye - ITT 
Population 
14.2.9.3 
Values and Mean Change from Screening Visit 2 in Central 
Retinal Lesion Thickness (µm) at 52 weeks in Subjects with 
Unilateral Disease– Fellow Eye - ITT Population 
14.2.10.1 
Values and Mean Change from Screening Visit 2 in Central 
Subfield Thickness (µm) at 52 weeks– Study Eye - ITT 
Population 
14.2.10.2 
Values and Mean Change from Screening Visit 2 in Central 
Subfield Thickness (µm) at 52 weeks– Fellow Eye - ITT 
Population 
14.2.10.3 
Values and Mean Change from Screening Visit 2 in Central 
Subfield Thickness (µm) at 52 weeks in Subjects with Unilateral 
Disease – Fellow Eye - ITT Population 
14.2.11.1 
Values and Mean Change from Screening Visit 2 in Macular 
Volume (mm3) at 52 weeks – Study Eye - ITT Population 
14.2.11.2 
Values and Mean Change from Screening Visit 2 in Macular 
Volume (mm3) at 52 weeks – Fellow Eye - ITT Population 
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Tyrogenex 
Version : FINAL 
X82-OPH-201 
Date: 11 September 2017 
14.2.11.3 
Values and Mean Change from Screening Visit 2 in Macular 
Volume (mm3) at 52 weeks in Subjects with Unilateral Disease – 
Fellow Eye - ITT Population 
14.2.12.1 
Values and Mean Change from Screening Visit 2 in Greatest 
Subretinal Fluid Height (µm) at 52 weeks– Study Eye - ITT 
Population 
14.2.12.2 
Values and Mean Change from Screening Visit 2 in Greatest 
Subretinal Fluid Height (µm) at 52 weeks– Fellow Eye - ITT 
Population 
14.2.12.3 
Values and Mean Change from Screening Visit 2 in Greatest 
Subretinal Fluid Height (µm) at 52 weeks in Subjects with 
Unilateral Disease– Fellow Eye - ITT Population 
14.2.13.1 
Presence of Subretinal Fluid at Screening Visit 2 and 52 weeks- 
Study Eye -  ITT Population 
14.2.13.2 
Presence of Subretinal Fluid at Screening Visit 2 and 52 weeks - 
Fellow Eye -  ITT Population 
14.2.13.3 
Presence of Subretinal Fluid at Screening Visit 2 and 52 weeks in 
Subjects with Unilateral Disease - Fellow Eye -  ITT Population 
14.2.14.1 
Values and Mean Change from Screening Visit 2 in Height of the 
RPE elevation(PED) (µm) at 52 weeks – Study Eye - ITT 
Population 
14.2.14.2 
Values and Mean Change from Screening Visit 2 in Height of the 
RPE elevation(PED) (µm) at 52 weeks – Fellow Eye - ITT 
Population 
14.2.14.3 
Values and Mean Change from Screening Visit 2 in Height of the 
RPE elevation(PED) (µm) at 52 weeks in Subjects with Unilateral 
Disease – Fellow Eye - ITT Population 
14.2.15.1 
Presence of Inter-Retinal Cysts at Screening Visit 2 and 52 
weeks – Study Eye - ITT Population 
14.2.14.2 
Presence of Inter-Retinal Cysts at Screening Visit 2 and 52 
weeks in Subjects with Unilateral Disease– Fellow Eye - ITT 
Population 
14.2.14.3 
Presence of Inter-Retinal Cysts at Screening Visit 2 and 52 
weeks in Subjects with Unilateral Disease – Fellow Eye - ITT 
Population 
14.2.15.1 
Conversion of Fellow Eye in Unilateral Subjects by 52 weeks – 
ITT Population 
14.2.16.1 
Mean Change from Baseline in VA at 52 weeks in Fellow Eye – 
ITT Population 
14.2.16.2 
Mean Change from Baseline in VA at 52 weeks in Fellow Eye in 
Subjects with Unilateral Disease – ITT Population 
14.2.17.1 
Anti-VEGF 
Injections 
received 
through 
52 
weeks 
after 
randomization in Fellow Eye – ITT Population 
14.2.17.2 
Anti-VEGF 
Injections 
received 
through 
52 
weeks 
after 
randomization in Fellow Eye in Subjects with Unilateral Disease– 
ITT Population 
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Tyrogenex 
Version : FINAL 
X82-OPH-201 
Date: 11 September 2017 
14.3.1.1 
Extent of Exposure – X-82 – SAF Population 
14.3.1.2 
Extent of Exposure – Anti-VEGF – SAF Population 
14.3.1.3 
Number of Missed Doses by Treatment and Overall by Visit and 
Overall- ITT Population 
14.3.1.4 
Number of Missed Doses by Subject by Visit and Overall 
14.3.1.5 
Summary of Food and Alcohol Intake - SAF Population 
14.3.2.1 
Summary of Treatment-Emergent Adverse Events – SAF 
Population 
14.3.2.2 
Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term – SAF Population 
14.3.2.3 
Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – SAF Population 
14.3.2.4 
Expected Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – SAF Population 
14.3.3.1 
Treatment-Emergent Adverse Events by Severity, by System 
Organ Class and Preferred Term – SAF Population 
14.3.3.2 
Related Treatment-Emergent Adverse Events by Severity, by 
System Organ Class and Preferred Term – SAF Population 
14.3.4.1 
Ophthalmic TEAEs by Preferred Term – Study Eye - SAF 
Population 
14.3.4.2 
Related Ophthalmic TEAEs by Preferred Term – Study Eye - SAF 
Population 
14.3.4.3 
Ophthalmic TEAEs by Preferred Term – Fellow Eye - SAF 
Population 
14.3.4.4 
Related Ophthalmic TEAEs by Preferred Term – Fellow Eye - SAF 
Population 
14.3.4.5 
Cardiovascular Adverse Events of Interest by Preferred Term- 
SAF Population 
14.3.5.1 
Treatment-Emergent Adverse Events leading to Permanent 
Discontinuation of Study Drug by System Organ Class and 
Preferred Term – SAF Population 
14.3.5.2 
Related 
Treatment-Emergent 
Adverse 
Events 
leading 
to 
Permanent Discontinuation of Study Drug by System Organ 
Class and Preferred Term – SAF Population 
14.3.6.1 
Treatment-Emergent Adverse Events Leading to Death by 
System Organ Class and Preferred Term – SAF Population 
14.3.6.2 
Related Treatment-Emergent Adverse Events Leading to Death 
by System Organ Class and Preferred Term – SAF Population 
14.3.7 
Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term – SAF Population 
14.3.8 
Deaths – SAF Population 
14.3.9.1 
Laboratory Data: Descriptive Statistics (Values and Changes 
from Baseline) by Visit – SAF Population 
14.3.9.2 
Laboratory Data: Descriptive Statistics (Frequencies per visit) – 
SAF Population 
14.3.9.3 
Laboratory Data: Baseline vs Worst Treatment-Emergent NCI-
CTC Grade – SAF Population 
14.3.9.4 
Laboratory 
Data: 
Baseline 
vs 
Worst 
Treatment-Emergent 
Abnormality Grade – SAF Population 
14.3.10 
Summary of Vital Signs by Visit – SAF Population 
14.3.11 
Summary of Ophthalmic Examination Results by Visit – Study 
Eye – SAF Population 
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Tyrogenex 
Version : FINAL 
X82-OPH-201 
Date: 11 September 2017 
14.3.12 
Tonometry Intraocular Pressure (IOP) Values and Changes from 
Baseline by visit – Study Eye - Safety Population 
14.3.13.1 
Shifts in 12-Lead ECG Status by Visit – SAF Population 
14.3.13.2 
Summary of 12-Lead ECG Parameters by Visit – SAF Population 
14.3.13.3 
Abnormal Values of 12-Lead ECG Parameters – SAF Population 
 
 
 
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Tyrogenex 
Version : FINAL 
X82-OPH-201 
Date: 11 September 2017 
11.2 
List of Graphs 
 
Graph Number 
Title 
14.2.1.1 
Mean change in VA over time in Study Eye – ITT Population 
14.2.1.2 
Mean change in VA over time in Study Eye – PP Population 
14.2.1.3 
Mean change in VA over time in Fellow Eye– ITT Population 
14.2.1.4 
Mean change in VA over time in Fellow Eye in Subjects with 
Unilateral Disease – ITT Population 
14.2.2.1 
Mean VA over time in Study Eye – ITT Population 
14.2.2.2 
Mean VA over time in Study Eye – PP Population 
14.2.2.3 
Mean VA over time in Fellow Eye – ITT Population 
14.2.2.4 
Mean VA over time in Fellow Eye in Subjects with Unilateral 
Disease – ITT Population 
14.2.3.1 
Number of Anti-VEGF Injections per Year in Study Eye – ITT 
population 
14.2.3.2 
Number of Anti-VEGF Injections per Year in Fellow Eye in 
Subjects with Unilateral Disease-ITT population 
14.2.3.3 
Number of Anti-VEGF Injections per Year in Fellow Eye - ITT 
population 
14.2.4.1 
Kaplan-Meier Plot of Time from Day 1 to First Anti-VEGF 
Injection – ITT Population 
14.3.1.1 
Mean Change in ALT (U/L) over time – SAF Population 
14.3.1.2 
Mean Change in AST (U/L) over time – SAF Population 
14.3.1.3 
Mean Change in WBC (THOU/MCL) over time – SAF Population 
14.3.1.4 
Mean Change in Absolute Neutrophil Count (THOU/MCL) over 
time – SAF Population 
14.3.1.5 
Mean Change in Absolute Lymphocyte Count (THOU/MCL) over 
time – SAF Population 
14.3.1.6 
Mean Change in Platelets (PER CUMM) over time – SAF 
Population 
14.3.1.7 
Mean Change in TSH (MCIU/ML) over time – SAF Population 
14.3.1.8 
Mean Change in Free T4 (NG/DL) over time – SAF Population 
14.3.1.9 
Mean Change in Total T3 (NG/DL) over time – SAF Population 
 
 
 
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Statistical Analysis Plan 
 
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Tyrogenex 
Version : FINAL 
X82-OPH-201 
Date: 11 September 2017 
11.3 
List of Derived Data Listings 
 
Listing 
Number 
Title 
16.1.1 
Listing of Premature Discontinuations of the Study – ITT 
Population 
16.1.2.1 
Listing of Protocol Deviation Details – ITT Population 
16.1.2.2 
Listing of Inclusion and Exclusion Criteria Not Met – ITT 
Population 
16.1.2.3 
Listing of Discrepancies between Stratification Factors in ID-net 
and MARVIN 
16.1.2.4 
Listing of Discrepancies between Retreatment Criteria and 
Retreatment by Applicable Protocol Amendment 
16.1.3 
Listing of Demographics and other Baseline Characteristics – ITT 
Population 
16.1.4.1 
Listing of Ocular History – ITT Population 
16.1.4.2 
Listing of Medical History – ITT Population 
16.1.5.1 
Listing of Prior and Concomitant Surgeries/Procedures – ITT 
Population 
16.1.5.2 
Listing of Prior and Concomitant Medications – ITT Population 
16.1.5.3 
Listing of Alcohol Intake with Study Medication – SAF Population 
16.2.1 
Listing of Visual Acuity – ITT Population 
16.2.3 
Listing of FA Parameters – ITT Population 
16.2.4 
Listing of SD-OCT Parameters – ITT Population 
16.2.5 
Listing of Subjects with Conversion of Fellow Eye by Week 52 
16.3.1.1 
Listing of Exposure to X-82 – SAF Population 
16.3.1.2 
Listing of anti-VEGF Exposure – SAF Population 
16.3.2.1 
Listing of Adverse Events – SAF Population 
16.3.2.2 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Drug – SAF Population 
16.3.2.3 
Listing of Adverse Events Leading to Death – SAF Population 
16.3.2.4 
Listing of Serious Adverse Events – SAF Population 
16.3.2.5 
Listing of Cardiovascular Adverse Events of Interest- SAF 
Population 
16.3.3 
Listing of Deaths – SAF Population 
16.3.4 
Listing of Laboratory Data –SAF Population 
16.3.5 
Listing of Vital Signs – SAF Population 
16.3.6 
Listing of Ophthalmic Examination Results – SAF Population 
16.3.7 
Listing of Tonometry Results – SAF Population 
16.3.8 
Listing of 12-Lead ECGs – SAF Population 
 
 
Tyrogenex - X82-OPH-201                                                                   Version: 4.0
.                                                            Approved in Vault: 9/11/2017