A Two-Year, Randomized, Double-Masked, Multicenter, Three-Arm Study Comparing the Efficacy and Safety of RTH258 Versus Aflibercept in Subjects With Neovascular Age-Related Macular Degeneration
Phase: PHASE3
Conditions: Neovascular Age-Related Macular Degeneration, Choroidal Neovascularization
Sponsor: Alcon Research

Page 1 of 84
a Novartis company
Short Title
Efficacy and Safety of RTH258 versus Aflibercept
Long Title
A Two-Year, Randomized, Double-Masked, Multicenter, Three-Arm Study 
Comparing the Efficacy and Safety of RTH258 versus Aflibercept in 
Subjects with Neovascular Age-Related Macular Degeneration
Protocol Number:
RTH258-C001 (formerly TDOC-0016528, Version 2.0)
Study Phase:
3
Sponsor Name and 
Address:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 76134-2099
Investigational Product:
RTH258 solution for intravitreal injection, 6 mg/50 µL and 3 
mg/50 µL
US IND# / EudraCT
IND# 112023 / 2014-004885-95
Indication Studied:
Neovascular Age-Related Macular Degeneration
Investigator Agreement:
I have read the clinical study described herein, recognize its 
confidentiality, and agree to conduct the described trial in 
compliance with Good Clinical Practices (GCP), the ethical 
principles contained within the Declaration of Helsinki, this 
protocol, and all applicable regulatory requirements.
Principal Investigator:
Signature
Date
Name:
Address:
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Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C001
lesions with a CNV component) in the study eye, confirmed by 
the Central Reading Center (CRC) at Screening
4. Total area of CNV (including both classic and occult 
components) must comprise > 50% of the total lesion area in the 
study eye, confirmed by the CRC at Screening
5. Intra and/or subretinal fluid affecting the central subfield of the 
study eye, confirmed by the CRC at Screening
6. BCVA between 78 and 23 letters, inclusive, in the study eye at 
Screening and Baseline using Early Treatment Diabetic 
Retinopathy Study (ETDRS) testing
Exclusion Criteria:
1. Any active intraocular or periocular infection or active 
intraocular inflammation (e.g. infectious conjunctivitis, keratitis, 
scleritis, endophthalmitis, infectious blepharitis) in either eye at 
Baseline
2. Central subfield of the study eye affected by fibrosis or 
geographic atrophy assessed by color fundus photography and 
confirmed by the CRC at Screening
3. Total area of fibrosis ≥ 50% of the total lesion in the study eye, 
confirmed by the CRC at Screening
4. Subretinal blood affecting the foveal center point and/or ≥ 50% 
of the lesion of the study eye, confirmed by the CRC at Screening
5. Subject has received any approved or investigational treatment 
for neovascular AMD (other than vitamin supplements) in the 
study eye at any time
6. Any history or evidence of a concurrent intraocular condition in 
the study eye, including retinal diseases other than neovascular 
AMD, that, in the judgment of the Investigator, could either 
require medical or surgical intervention during the course of the 
study to prevent or treat visual loss that might result from that 
condition or that limits the potential to gain visual acuity upon 
treatment with the investigational product 
7. Retinal pigment epithelium (RPE) rip/tear in the study eye at 
Screening or Baseline
8. Current vitreous hemorrhage or history of vitreous hemorrhage 
in the study eye within 4 weeks prior to Baseline 
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Page 6 of 84
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C001
9. History or evidence of the following in the study eye:
• intraocular or refractive surgery within the 90 day period 
prior to Baseline
• previous penetrating keratoplasty or vitrectomy
• previous panretinal photocoagulation
• previous submacular surgery, other surgical intervention 
or laser treatment for AMD
10. Uncontrolled glaucoma in the study eye defined as intraocular 
pressure (IOP) > 25 mmHg on medication or according to 
Investigator’s judgment at Screening or Baseline
11. Aphakia and/or absence of the posterior capsule in the study 
eye at Screening or Baseline
12. Intra- or periocular use of corticosteroids in the study eye 
during the 6 month period prior to Baseline 
13. Use of topical ocular corticosteroids in the study eye for 60 or 
more consecutive days within the 90 day period prior to Baseline 
14. Use of systemic corticosteroids for 30 or more consecutive 
days within the 90 days prior to Baseline, with the exception of 
low stable doses of corticosteroids (defined as ≤10 mg 
prednisolone or equivalent dose used for 90 days or more). 
Inhaled, nasal or dermal steroids are permitted
15. Previous therapeutic radiation near the region of the study eye
16. Treatment with aflibercept (EYLEA®), bevacizumab 
(AVASTIN®) or pegaptanib (MACUGEN®) within the 4 week 
period prior to Baseline, or with ranibizumab (LUCENTIS®) 
within the 2 week period prior to Baseline in the nonstudy eye
17. History of a medical condition (disease, metabolic 
dysfunction, physical examination finding, or clinical laboratory 
finding) that, in the judgment of the Investigator, would preclude 
scheduled study visits, completion of the study, or a safe 
administration of investigational product
18. History of hypersensitivity to any component of the test 
article, control article, or clinically relevant sensitivity to 
fluorescein dye (or indocyanine green for subjects in Japan), as 
assessed by the Investigator
19. Pregnant or nursing (lactating) women, where pregnancy is 
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Page 7 of 84
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C001
defined as the state of a female after conception and until 
termination of gestation, confirmed by a positive hCG pregnancy 
test and women of child-bearing potential, defined as all women 
less than 1 year postmenopausal or less than 6 weeks since 
sterilization at Baseline, unless they are using effective methods of 
contraception during dosing of study treatment. Effective
contraception methods include:
• Total abstinence (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of 
contraception
• Female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or tubal 
ligation at least 6 weeks before Baseline. In case of 
oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone 
level assessment
• Male sterilization (at least 6 months prior to Baseline). 
For female subjects in the study, the vasectomized male 
partner should be the sole partner for that subject
• Barrier methods of contraception: condom or occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository
• Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception 
that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone 
contraception
• Placement of an intrauterine device (IUD) or intrauterine 
system (IUS)
20. Participation in an investigational drug, biologic, or device 
study within 30 days or the duration of 5 half-lives of the 
investigational product (whichever is longer) prior to Baseline 
Note: observational clinical studies solely involving over-the-
counter vitamins, supplements, or diets are not exclusionary 
21. Systemic anti-vascular endothelial growth factor (VEGF) 
therapy within the 90 day period prior to Baseline 
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Page 11 of 84
Sponsor:
Alcon Research, Ltd.
6201 South Freeway
Fort Worth, Texas 
76134-2099
Protocol Number: RTH258-C001
(PPS) and alternative imputation for missing values including a 
mixed model repeated measures (MMRM) and observed data only 
analyses.
Statistical testing strategy:  
The 4 hypotheses will be tested in the pre-specified hierarchical 
sequence according to their numbering (HAn, n=1,2,3,4). 
Consequently, confirmatory testing of a given hypothesis requires 
rejection of all preceding null hypotheses. In this setting, each 
hypothesis will be assessed at a two-sided α = 0.05, while keeping 
the global type I error rate at 0.05.
Statistical method: 
Two-sided 95% confidence intervals (CI) for the differences in 
means, RTH258 – aflibercept, based on an analysis of variance 
(ANOVA) model with treatment, Baseline BCVA categories (≤ 
55, 56-70, ≥71 letters), and age categories (< 75, ≥ 75 years) as 
fixed effects will be presented for the primary efficacy analysis. 
The same ANOVA model will be fitted for the key secondary 
endpoint, average change in BCVA from Baseline over the period 
Week 36 through 48.
Within the specified hierarchical testing strategy, noninferiority 
will be established if the lower limit of the corresponding 95% CI 
is greater than -4 letters (corresponding to the noninferiority 
margin of 4 letters). 
Sample size: 
A sample size of 297 subjects per treatment arm is sufficient to 
demonstrate noninferiority (margin = 4 letters) of RTH258 6 mg/3 
mg versus aflibercept 2 mg with respect to the BCVA change 
from Baseline to Week 48 at a two-sided alpha level of 0.05 with 
a power of approximately 90% assuming equal efficacy and a 
common standard deviation of 15 letters. A power of at least 90% 
can be expected for the first key secondary endpoint assuming that 
averaging over the 4 time points will not lead to an increase in the 
standard deviation.
To account for a drop-out rate of 10%, a total of 330 subjects will 
be randomized per treatment arm. 
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Page 12 of 84
1.1
Amendments
Amendment 4
Purpose of amendment:
The primary purpose of this amendment is to add back missing text in section 11.3. This text 
was available in the original protocol, however due to technical issues was accidentally 
removed and is being added back now. In addition, other minor clarifications have been 
added to sections 10.5, 10.6, 10.7.4, 12.3.
Amendment 3
Purpose of amendment:
The primary purpose of this amendment is to allow ADA analysis of the samples collected 
from aflibercept treated patients (Section 10.7.5). Minor clarifications have also been made to 
Sections 9.4, 10.1, 10.9 and 12.3
Amendment 2
Note: This TDOC-0050793 was formerly TDOC-0016528, Version 2.0. The change in 
document numbers was due to a new document management system.
Purpose of the Amendment:
The primary purpose of this amendment is to incorporate changes which resulted from 
interactions with Regulatory Authorities. In addition, changes have been made to clarify 
some inclusion/exclusion criteria and study procedures.
Rationale:
Revision 1 (Section 1. Synopsis, Section 2. Overview of Study Plan, Section 10.2.1. 
Screening Visit (Day -14 to Day -2) and Section 10.2.2. Visit 1/Baseline (Day 0)): Require 
BCVA in the study eye to be between 78 and 23 letters, inclusive, at Screening as well as 
Baseline.
Rationale: The purpose of this change is to further clarify the intention of the protocol that 
the criterion must be met at both the Screening and Baseline Visit by stating it explicitly.
Revision 2 (Section 1. Synopsis): The term central subfield in exclusion criteria number 4 
was changed to foveal center point.
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Page 13 of 84
Rationale: The current wording excludes subjects who are appropriate for anti-VEGF 
treatment. The change is intended to reduce unnecessary screen failures.
Revision 3 (Section 1. Synopsis, Section 2. Overview of Study Plan, Section 10.2.2. Visit 
1/Baseline (Day 0), Section 10.2.3. Visit 2/Week 4 (Day 28 ± 3 Days) and Visit 3/Week 8 
(Day 56 ± 3 Days), Section 10.2.4. Visit 4 (Visit 3 + 1 day) and Section 10.7.5. Analysis of 
Anti-Drug Antibodies (ADA), Systemic RTH258 and Accumulation (Cmax) of RTH258): 
Removal of Visit 4 (blood draw for accumulation (Cmax) of RTH258 1 day after the third 
loading dose) from the protocol.
Rationale: This pharmacological assessment will be conducted in another study.
Revision 4 (Section 2. Overview of Study Plan and Section 10.2.3. Visit 2/Week 4 (Day 28 ± 
3 Days) and Visit 3/Week 8 (Day 56 ± 3 Days): Addition of blood draw for ADA and 
Systemic RTH258 testing to Visit 2/Week 4. 
Rationale: These tests were added to evaluate the early systemic immune response to the 
initial intravitreal dose of RTH258 and to determine the systemic exposure of the drug. 
Revision 5 (Section 2. Overview of Study Plan and Section 10.7.16 Postinjection 
Assessment): Simplification of the postinjection assessment.
Rationale: This change is to make post injection fundoscopy at the discretion of the 
investigator, thereby reducing the risk of postinjection IOP rise due to pupil dilation.
Revision 6 (Section 10.8. Concomitant Treatment and Section 10.9. Prohibited Treatment): 
Allowance of all treatments in the nonstudy eye which are approved for exudative AMD in 
the respective country.
Rationale: This change has been made to ensure subjects have unrestricted access to 
standard of care treatment in the nonstudy eye. 
Revision 7 (Section 13.5. Data Monitoring Committee): Addition of a Data Monitoring 
Committee (DMC).
Rationale: During the Voluntary Harmonization Procedure (VHP) for the RTH258-C002 
study, the VHP committee requested that a DMC be established for the C002 study. This 
DMC will also be utilized to monitor the safety data from study RTH258-C001.
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Page 16 of 84
10.2.2. VISIT 1/BASELINE (DAY 0)
Paragraphs removed/modified:
Subject eligibility will be determined at Screening. However, if the BCVA is not able to be 
assessed at the Screening Visit, the Baseline Visit BCVA may be used to qualify the subject. 
Baseline BCVA of the study eye must be between 78 and 23 letters, inclusive, for the subject 
to qualify.
At the Baseline Visit, subjects will be randomized only if the subject has successfully met all 
of the eligibility criteria.
At the Baseline Visit IRT will also randomly assign approximately 72 subjects
(approximately 24 in each treatment arm; half from Japanese sites and half from non
Japanese sites) to have blood draws for accumulation (Cmax) of RTH258 at Visit 4 (Week 8 
+ 1 day).
12. Contact IRT to obtain a kit number. IRT will also randomly select a subset of subjects to 
attend Visit 4 (Visit 3+1 day). If the subject is selected for this visit the IRT system will notify 
the user during this transaction.
13. Have the unmasked Investigator perform an IVT injection according to the 
randomization/kit assignment. The injection procedure may be performed at a later time as 
long as it occurs within 7 days of the scheduled visit. and within the visit window.
10.2.3. VISIT 2/WEEK 4 (DAY 28 ± 3 DAYS) AND VISIT 3/WEEK 8 (DAY 56±3 DAYS)
Added:
4. Obtain a blood sample for ADA analysis (Visit 2 only). Blood draws should take place 
prior to the IVT injection.
5. Obtain a blood sample for systemic RTH258 analysis (Visit 2 only). Blood draws should 
take place prior to the IVT injection.
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Page 17 of 84
Changed:
12. 10. Schedule Visit 4 to take place 1 day after Visit 3 if the subject has been pre
determined by IRT to attend Visit 4. Otherwise, schedule Visit 5/Week 12 to take place 84 ± 7 
days after Visit 1/Baseline.
10.2.4. VISIT 4 (VISIT 3 + 1 DAY)
Changed:
This visit only applies to the subset of subjects who were randomly selected to attend it and 
did so before Version 3.0 of the protocol became effective. 
This visit will be performed on a subset of subjects as determined by IRT.
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Record any AEs that are observed or reported, including those associated with 
changes in concomitant medication dosing.
3. Obtain a blood sample for Cmax RTH258 analysis.
4. Schedule Visit 5/Week 12 to take place 84 ± 7 days after Visit 1/Baseline.
10.7.5. ANALYSIS OF ANTI-DRUG ANTIBODIES (ADA), Systemic RTH258 and 
accumulation (Cmax) of RTH258
Changed:
10.7.5. ANALYSIS OF ANTI-DRUG ANTIBODIES (ADA), and Systemic RTH258 and 
accumulation (Cmax) of RTH258
Collection of blood for ADA, and systemic RTH258, and the accumulation (Cmax) of 
RTH258 should take place prior to any injection/sham. A standardized procedure for the 
collection, processing, storage and shipment of these blood samples is provided in a separate 
laboratory hand book.
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Page 18 of 84
Only samples from RTH258 treated subjects will be analyzed for ADA, and systemic 
RTH258. and accumulation (Cmax) of RTH258.
10.7.16. POSTINJECTION ASSESSMENT
First paragraph changed:
The study eye will be assessed before, immediately (0-5 minutes) after and 30 (± 15) minutes 
after each IVT/sham injection to ensure that the procedure and/or the study medication have 
not endangered the health of the eye. The postinjection assessments include an evaluation of 
central retinal artery perfusion via a gross assessment of vision (eg, count fingers), the status 
of the central retinal artery, presence of retinal detachment, presence of new intraocular 
hemorrhage(s) and measurement of IOP according to the schedule detailed in the MOP. 
Direct visualization to assess the central retinal artery, presence of retinal detachment, 
presence of new intraocular hemorrhage(s) might be appropriate at the discretion of the 
investigator and/or based on the results of gross assessment of vision and IOP measurement.
10.8. Concomitant Treatment
Changed to:
The Investigator should instruct the subject to notify the study site about any new 
medications he/she takes after enrolling into the study.
Should the nonstudy eye require treatment during the study with an anti-VEGF, ranibizumab 
a drug which is approved for the treatment of exudative AMD in the respective country
should be applied at the discretion of the Investigator and following the procedures 
established at the respective site. The nonstudy eye treatment may occur at any time once the 
Baseline study eye injection has been administered.
Table 10-1: Prohibited Treatment
Nonstudy eye treatment changed to:
Nonstudy eye: Unapproved or Investigational treatment Anti VEGF therapy other than 
ranibizumab
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13.5. Data Monitoring Committee
Section added:
An independent Data Monitoring Committee (DMC) will be established to monitor the safety 
of the trial participants, to ensure that the trial is being conducted with the highest scientific 
and ethical standards, and make appropriate recommendations based on the data seen. 
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communications 
with the Sponsor. The DMC will only make recommendations for changes in study conduct.
Amendment 1
Purpose of Amendment:
The primary purpose of this amendment is to implement required changes received from 
regulatory authorities. In addition, the data collection and analysis plan has been changed to 
improve the reporting of the q12 (treatment every 12 weeks) potential of RTH258 and also 
clarifications and corrections were implemented based on feedback from key opinion leaders 
and the CRC.
Rationale:
Revision 1 (Section 1. Synopsis and Section 11. Analysis Plan): Methodology, endpoints and 
statistical methods were revised.
Rationale: These revisions were made to repeat the analyses performed at Week 48 at the 
end of the study, and to align with variables measured by the CRC.
Revision 2 (Section 1. Synopsis): The terms fovea and central fovea in the inclusion and 
exclusion criteria were changed to central subfield.
Rationale: The CRC will use the central subfield for assessing eligibility; this modification 
was made to provide clarity to Investigators.
Revision 3 (Section 1. Synopsis): Use of pegaptanib (MACUGEN®) within 4 weeks prior to 
Baseline added as an excluded medication.
Rationale: This addition was made to avoid unnecessary exclusion of subjects with prior 
exposure to pegaptanib, which is still used in some countries.
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Page 20 of 84
Revision 4 (Section 1. Synopsis): Hypersensitivity to povidone iodine was removed as an 
exclusion.
Rationale: Other options are available for preparation of the eye for IVT injection and 
therefore the original exclusion was unnecessarily restrictive.
Revision 5 (Section 1. Synopsis): Pregnant and nursing (lactating) women were added to the 
exclusion criterion.
Rationale: These exclusions were requested by the Japanese Regulatory Authority.
Revision 6 (Section 1. Synopsis and Section 11.3. Analysis Set): Definition of full analysis set 
was revised to include all subjects who are randomized and receive at least one IVT injection.
Rationale: This change was requested by the United States Regulatory Agency.
Revision 7 (Section 2. Overview of Study Plan): Study procedures were revised to state that 
all blood draws and collection of urine samples should occur prior to subjects receiving an 
IVT or sham injection or injection of fluorescein dye.
Rationale: IVT injection or injection of fluorescein prior to collection of the laboratory 
samples could confound the results.
Revision 8 (Section 2. Overview of Study Plan and Section 10.2.5. Visit 5/Week 12 through 
Visit 25/Week 92): Fluorescein angiography and color fundus photography were added to 
Visit 5/Week 12.
Rationale: An early assessment (Week 12) of fluorescein angiography will allow capture of 
RTH258 impact on lesion activity compared to aflibercept. Week 12 color fundus 
photography will allow early assessment of geographic atrophy and identify subjects who 
have lesions which may have been masked by an increased retinal thickness at Baseline.
Revision 9 (Section 2. Overview of Study Plan, Figure 10.1.-1: Dosing Schedule by 
Treatment, Section 10.2.5. Visit 5/Week 12 through Visit 25/Week 92 and Section 10.7.13. 
Disease Activity Assessment): Disease activity assessment added to Week 92. 
Rationale: This addition will have no impact on the treatment regimen but will allow the 
proportion of subjects who can be treated q12 to be estimated at the end of the study 
(RTH258 3 and 6 mg arms only).
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Revision 10 (Section 2. Overview of Study Plan, Section 10.2.2. Visit 1/Baseline, Section 
10.2.3. Visit 2/Week 4 and Visit 3/Week 8 and Section 10.2.5. Visit 5/Week 12 through Visit 
25/Week 92): Period that the injection may be performed after the scheduled visit was 
extended from 48 hours to 7 days as long as the injection is performed within the visit 
window.
Rationale: This revision was made to allow more flexibility at the investigative sites while 
not compromising the study data.
Revision 11 (Section 10.2.1. Screening Visit): Allowance for screening procedures to be 
conducted over more than 1 day was added.
Rationale: Due to the number and complexity of screening procedures it was determined that 
it would be beneficial to investigative sites to allow screening to take place over multiple 
days and will not compromise validity of screening data.
Revision 12 (Section 10.2.1. Screening Visit): Criteria for rescreening were added.
Rationale: These criteria were added to clarify the circumstances under which subjects can 
be rescreened.
Revision 13 (Section 10.2.1. Screening Visit): The option for a legally authorized 
representative to sign the informed consent form was removed.
Rationale: This was removed because it was decided that signing of the informed consent 
form by a legally authorized representative was not appropriate for this trial.
Revision 14 (Section 10.9. Prohibited Treatment): The allowance for administration of low 
stable doses of corticosteroids to subjects during the course of the study was added.
Rationale: This was added to clarify and align with the inclusion criteria.
Revision 15 (Section 11.4.2. Baseline Characteristics): The following baseline characteristics 
were deleted from the analyses: cyst volume, hyperreflective material, presence of intraocular 
hemorrhage and central subfield volume.
Rationale: This modification was made to align with the variables captured by the CRC.
Revision 16 (Section 12.3. Procedures for Recording and Reporting AEs and SAEs): The 
language regarding adverse events of special interest relative to intraocular inflammation 
were revised.
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Page 26 of 84
10.2 SCREENING VISIT (DAY -14 TO DAY -2)
Added:
The completion of assessments for this visit may occur on different days. The screening 
period starts with the first screening procedure (other than signing of the ICF). 
One time rescreening of subjects will be allowed in the following circumstances: a) 
laboratory test(s) need to be repeated, b) when a subject has a temporary medical condition 
precluding participation. As long as testing can be repeated within 14 days of the first 
screening, the other screening assessments do not need to be repeated. If rescreening is to 
occur beyond 14 days from the original screening visit date, then all screening procedures 
must be repeated. Rescreening will not be permitted for the purpose of capturing new BCVA 
or imaging assessments that previously failed to qualify the subject. Medical judgment should 
be exercised to ensure that treatment is not withheld in order for a subject  to participate in 
the study.
10.7.13 DISEASE ACTIVITY ASSESSMENT
Section revised:
The masked Investigator will assess the study eye of all subjects at Visit 6/Week 16, Visit 
7/Week 20, Visit 10/Week 32, Visit 13/Week 44, Visit 16/Week 56, Visit 19/Week 68 and 
Visit 22/Week 80. If the subject presents with new or worsening disease activity, as defined in 
Section 10.1, tThe IRT system will make the necessary changes to the dosing per the masked 
Investigator’s assessment. assign the subject to q8 treatment for the remainder of the study.
The disease activity assessment will also be performed at Visit 25/Week 92, but will not be 
entered into IRT and will have no effect on the subject’s treatment regimen. Details of the 
disease activity assessments are further outlined in the MOP.
11.3 Analysis Sets
Definitions for full analysis set and per protocol analysis set revised:
Full analysis set (FAS): includes all subjects who are randomized, and received at least one 
IVT injection and have a baseline and at least 1 postbaseline measurement of BCVA. 
Following the intent-to-treat (ITT) principle, subjects in the FAS will be analyzed according 
to the treatment group they are assigned at randomization, regardless of whether dosing 
frequency  (q12 to q8) changed at subsequent visits. The FAS will be the primary analysis set 
for efficacy analyses.
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Page 31 of 84
2
OVERVIEW OF STUDY PLAN
Screening
Visit 1/
Baseline
Visit 
2/
Week 
4
Visit 
3/
Week 
8
Visit 
47
Visit 
5/
Week 
12
Visit 
6/
Week 
16
Visit 
7/
Week 
20
Visit 
8/
Week 
24
Visit 
9/
Week 
28
Visit 
10/
Week 
32
Visit 
11/
Week 
36
Visit 
12/
Week 
40
Visit 
13/
Week 
44
Visit 
14/
Week 
48
Day
-14 to -2
Day 0
Day
28 ± 3
Days
Day
56 ± 3
Days
Visit 3
+ 1 
Day
Day
84 ± 7
Days
Day
112 ± 
7
Days
Day
140 ± 
7
Days
Day
168 ± 
7
Days
Day
196 ± 
7
Days
Day
224 ± 
7
Days
Day
252 ± 
7
Days
Day
280 ± 
7
Days
Day
308 ± 
7
Days
Day
336 ± 
7
Days
Informed Consent1
X
Demographics
X
Medical History/ 
Concomitant 
Medications
X
Changes in 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitor for Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/ Exclusion
X
X2
Visual Function 
Questionnaire-25 
(VFQ-25)3
X
X
X
General Physical 
Exam4
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test5
X
X
Blood/Urine 
Sample: Chemistry/ 
Hematology/ 
Urinalysis6
X
X
X
Blood Draw for 
Anti-Drug 
Antibodies (ADA)6
X
X
X
X
X
X
Blood Draw for 
Systemic RTH2586
X
X
X
X
X
X
Best-Corrected 
Visual Acuity 
(BCVA)
X8
X8
X
X
X8
X
X
X8
X
X
X8
X
X
X8
Complete 
Ophthalmic Exam9
X8
X
X
X
X
X
X
X
X
X
X
X
X
X8
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Screening
Visit 1/
Baseline
Visit 
2/
Week 
4
Visit 
3/
Week 
8
Visit 
47
Visit 
5/
Week 
12
Visit 
6/
Week 
16
Visit 
7/
Week 
20
Visit 
8/
Week 
24
Visit 
9/
Week 
28
Visit 
10/
Week 
32
Visit 
11/
Week 
36
Visit 
12/
Week 
40
Visit 
13/
Week 
44
Visit 
14/
Week 
48
Day
-14 to -2
Day 0
Day
28 ± 3
Days
Day
56 ± 3
Days
Visit 3
+ 1 
Day
Day
84 ± 7
Days
Day
112 ± 
7
Days
Day
140 ± 
7
Days
Day
168 ± 
7
Days
Day
196 ± 
7
Days
Day
224 ± 
7
Days
Day
252 ± 
7
Days
Day
280 ± 
7
Days
Day
308 ± 
7
Days
Day
336 ± 
7
Days
Spectral Domain 
Optical Coherence 
Tomography (SD-
OCT)
X8
X
X
X
X
X
X
X
X
X
X
X
X
X8
Fluorescein 
Angiography (FA)10
X8
X
X8
Color Fundus 
Photography
X8
X
X8
Indocyanine Green 
(ICG)11
X8
Fundus 
Autofluorescence 
(FAF)12
X12
X12
X12
Disease Activity 
Assessment 
X
X
X
X
Contact Interactive 
Response 
Technology (IRT)
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer Study 
Injection or Sham13/ 
Postinjection 
Assessment14
X
X
X
X
X
X
X
X
X
X
X
X
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Visit 
15/
Week 
52
Visit 
16/
Week 
56
Visit 
17/
Week 
60
Visit 
18/
Week
64
Visit 
19/
Week 
68
Visit 
20/
Week 
72
Visit 
21/
Week 
76
Visit 
22/
Week 
80
Visit 
23/
Week 
84
Visit 
24/
Week 
88
Visit 
25/
Week 
92
Visit 
26/
Week 
96 / 
Exit15
Day
364 ± 
7
Days 
Day
392 ± 
7
Days
Day
420 ± 
7
Days
Day
448 ± 
7
Days
Day
476 ± 
7
Days
Day
504 ± 
7
Days
Day
532 ± 
7
Days
Day
560 ± 
7
Days
Day
588 ± 
7
Days
Day
616 ± 
7
Days
Day
644 ± 
7
Days
Day
672 ± 
7
Days
Changes in Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
Monitor for Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
Visual Function 
Questionnaire-25 (VFQ-
25) 3
X
X
General Physical Exam4
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy  
Test5
X
Blood/Urine Sample: 
Chemistry/ Hematology/ 
Urinalysis6
X
Blood Draw for Anti-Drug 
Antibodies (ADA)6
X
X
(X)16
Blood Draw for Systemic 
RTH2586
X
X
(X)16
Best-Corrected Visual 
Acuity (BCVA)
X
X
X8
X
X
X8
X
X
X8
X
X
X8
Complete Ophthalmic 
Exam9
X
X
X
X
X
X
X
X
X
X
X
X8
Spectral Domain Optical 
Coherence Tomography 
(SD-OCT)
X
X
X
X
X
X
X
X
X
X
X
X8
Fluorescein Angiography 
(FA)10
X8
Color Fundus Photography
X8
Fundus Autofluorescence 
(FAF)12
X12
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Visit 
15/
Week 
52
Visit 
16/
Week 
56
Visit 
17/
Week 
60
Visit 
18/
Week
64
Visit 
19/
Week 
68
Visit 
20/
Week 
72
Visit 
21/
Week 
76
Visit 
22/
Week 
80
Visit 
23/
Week 
84
Visit 
24/
Week 
88
Visit 
25/
Week 
92
Visit 
26/
Week 
96 / 
Exit15
Day
364 ± 
7
Days 
Day
392 ± 
7
Days
Day
420 ± 
7
Days
Day
448 ± 
7
Days
Day
476 ± 
7
Days
Day
504 ± 
7
Days
Day
532 ± 
7
Days
Day
560 ± 
7
Days
Day
588 ± 
7
Days
Day
616 ± 
7
Days
Day
644 ± 
7
Days
Day
672 ± 
7
Days
Disease Activity 
Assessment 
X
X
X
X
Contact Interactive 
Response Technology 
(IRT)
X
X
X
X
X
X
X
X
X
X
X
Administer Study 
Injection or Sham13/ 
Postinjection Assessment14
X
X
X
X
X
X
X
X
X
X
X
Complete Exit Form15
X
1. The informed consent form must be signed/dated prior to performing any study procedures, including screening procedures.
2. Verify that inclusion/exclusion criteria are met at Visit 1/Baseline prior to assignment of study treatment.
3. Questionnaires are to be administered at those sites where validated translations are available and where they are approved by the corresponding Independent 
Ethics Committee/Institutional Review Board (IEC/IRB). Questionnaires must be administered prior to any examination.
4. All clinically significant findings will be recorded as medical history or adverse events, as appropriate. 
5. Required for all female subjects of childbearing potential. Urine pregnancy tests will be performed unless local regulations require a serum pregnancy test.
6. All blood draws and urine collections should be performed prior to receiving the IVT or sham injection and prior to injection of fluorescein dye.
7. Visit 4/Visit 3+1 day only applies to the subset of subjects who were randomly selected to complete it and did so before Version 3.0 of the protocol became 
effective.
8. Both eyes; all other assessments are study eye only.
9. Includes slit-lamp exam, IOP measurement, and fundus exam. Dilation for the fundus exam is at the discretion of the Investigator.
10. Other FA assessments, done outside of the visit schedule, may be performed at Investigator’s discretion based on exam findings, observations, etc.
11. ICG imaging applies to subjects screened at sites in Japan only.
12. FAF will be performed at a subset of sites.
13. Subjects will be randomized to one of the following treatments: RTH258 3 mg, RTH258 6 mg, or aflibercept 2 mg. Beginning at Week 16, when subjects do 
not receive an active injection, they will receive a sham injection. The injection may be performed at a later time, as long as it is within 7 days of the scheduled 
visit and within the visit window.
14. Whether the subject receives an active or sham injection, the study eye will be evaluated 0-5 minutes and 30 (±15) minutes postinjection to ensure that the 
injection procedure and/or the investigational product have not endangered the health of the eye. This includes an evaluation of central retinal artery perfusion via
gross assessment of vision and measurement of IOP. Direct visualization to assess the central retinal artery, presence of retinal detachment and presence of new 
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Page 35 of 84
intraocular hemorrhage(s) might be appropriate at the discretion of the investigator and/or based on the results of gross assessment of vision and IOP 
measurement.
15. All exit procedures should be followed, regardless of when the subject exits the study.
16. Blood draws for ADA and systemic RTH258 will be performed if the subject exits at or before Visit 24/Week 88.
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3
ABBREVIATIONS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
AEF
Adverse event form
AMD
Age-related macular degeneration
ANOVA
Analysis of variance
BCVA
Best-corrected visual acuity
CI
Confidence interval
CNV
Choroidal neovascularization
CRC
Central reading center
CRF
Case report form
CSFT
Central subfield thickness
CSM
Clinical site management
CTM
Clinical trial management
DEP
Deviations and evaluability plan
DMC
Data Monitoring Committee
EDC
Electronic data capture
ESI
Event of special interest
ETDRS
Early treatment diabetic retinopathy study
FA
Fluorescein angiography
FAF
Fundus autofluorescence
FAS
Full analysis set
GCP
Good clinical practice
ICF
Informed consent form
ICG
Indocyanine green
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IOP
Intraocular pressure
IP
Investigational product
IRB 
Institutional review board
IRC
Intraretinal cysts
IRF
Intraretinal fluid
IRT
Interactive response technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
IVT
Intravitreal
LOCF
Last observation carried forward
mg
Miligram
mL
Milliliter
mmHg
Millimeters of mercury
MMRM
Mixed model repeated measures
MOP
Manual of procedures
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Abbreviation
Definition
PCV
Polypoidal choroidal vasculopathy
PPS
Per protocol analysis set
PRN
Pro re nata
q8
Every 8 weeks
q12
Every 12 weeks
RAP
Retinal angiomatous proliferation
RPE
Retinal pigment epithelium
SAE
Serious adverse event
SAP
Statistical analysis plan
scFv
Single chain variable fragment
SD-OCT
Spectral-domain optical coherence tomography
SUSAR
Suspected unexpected serious adverse reaction
µL
Microliter
VEGF
Vascular endothelial growth factor
VFQ-25
Visual Function Questionnaire
VHP
Voluntary Harmonization Process
Glossary of Terms
Term
Definition
AMD
Clinical and/or angiographic signs of retinal degeneration (including drusen, 
hypo- or hyper-pigmentation, geographic atrophy, and choroidal 
neovascularization) with no other likely etiologic explanations for the 
degenerative changes
Central 
Subfield
The circular area within 1 mm diameter around the foveal center on imaging
CNV 
(subfoveal) 
secondary to 
AMD
Angiographic evidence of new blood vessel growth within the central 
subfield. The lesion containing the new vessel growth may be classic and/or 
occult and can include thick contiguous blood or an area of elevated blocked 
fluorescence corresponding to pigment that obscures the boundaries of the 
neovascular components, or serous detachment of the retinal pigment 
epithelium
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4
TABLE OF CONTENTS
1
SYNOPSIS .............................................................................................................2
1.1
Amendments.....................................................................................................12
2
OVERVIEW OF STUDY PLAN..........................................................................31
3
ABBREVIATIONS...............................................................................................36
4
TABLE OF CONTENTS......................................................................................38
List of Tables............................................................................................................................40
List of Figures..........................................................................................................................40
5
INTRODUCTION................................................................................................41
5.1
Study Rationale and Background .....................................................................41
5.1.1
Dose Rationale..............................................................................................43
5.1.2
Treatment Regimen Rationale......................................................................43
5.2
Benefits and Potential Risks.............................................................................44
6
ETHICS ................................................................................................................45
7
PROTOCOL AMENDMENTS ............................................................................46
8
SUBJECT POPULATION....................................................................................46
9
TREATMENTS ADMINISTERED......................................................................46
9.1
Identity of Study Treatments ............................................................................46
9.2
Usage ................................................................................................................47
9.3
Accountability Procedures................................................................................48
9.4
Subject Confidentiality and Methods Used to Minimize Bias .........................48
10
STUDY PROCEDURES ......................................................................................50
10.1
Outline of Study ...............................................................................................50
10.2
Visits and Examinations ...................................................................................52
10.2.1
Screening Visit (Day -14 to Day -2).............................................................52
10.2.2
Visit 1/Baseline (Day 0) ...............................................................................54
10.2.3
Visit 2/Week 4 (Day 28 ± 3 Days) and Visit 3/Week 8 (Day 56 ± 3 Days)..55
10.2.4
Visit 4 (Visit 3 + 1 Day) ...............................................................................56
10.2.5
Visit 5 /Week 12 (Day 84 ± 7 Days) Through Visit 25 /Week 92 (Day 644 ± 
7 Days)..........................................................................................................56
10.2.6
Visit 26/Week 96/Exit Visit (Day 672 ± 7 Days) or Early Exit....................58
10.3
Unscheduled Visits ...........................................................................................59
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10.4
Discontinued Subjects ......................................................................................59
10.5
Discontinuation of Study Treatment.................................................................60
10.6
Clinical Study Termination...............................................................................60
10.7
Study Methods and Measurements...................................................................61
10.7.1
Visual Function Questionnaire-25................................................................61
10.7.2
General Physical Exam and Vital Signs .......................................................61
10.7.3
Pregnancy Test..............................................................................................61
10.7.4
Laboratory Analysis of Blood and Urine......................................................62
10.7.5
Analysis of Anti-drug Antibodies (ADA) and Systemic RTH258 ...............62
10.7.6
Best-Corrected Visual Acuity.......................................................................62
10.7.7
Complete Ophthalmic Examination .............................................................62
10.7.8
Spectral Domain Optical Coherence Tomography Imaging.........................63
10.7.9
Fluorescein Angiography..............................................................................63
10.7.10
Color Fundus Photography...........................................................................63
10.7.11
Indocyanine Green........................................................................................63
10.7.12
Fundus Autofluorescence .............................................................................64
10.7.13
Disease Activity Assessment ........................................................................64
10.7.14
Intravitreal Administration of Investigational Product.................................64
10.7.15
Administration of Sham Injection ................................................................64
10.7.16
Postinjection Assessment..............................................................................64
10.8
Concomitant Treatment ....................................................................................65
10.9
Prohibited Treatment ........................................................................................65
11
ANALYSIS PLAN ...............................................................................................66
11.1
General Considerations ....................................................................................66
11.2
Subject Evaluability..........................................................................................66
11.3
Analysis Sets ....................................................................................................66
11.4
Demographic and Baseline Characteristics......................................................67
11.4.1
Demographic Characteristics........................................................................67
11.4.2
Baseline Characteristics................................................................................67
11.5
Primary and Key Secondary Efficacy Analyses...............................................68
11.5.1
Statistical Hypotheses...................................................................................68
11.5.2
Statistical Methods .......................................................................................69
11.5.3
Sensitivity Analyses......................................................................................70
11.5.4
Subgroups.....................................................................................................70
11.6
Additional Secondary Efficacy Analyses .........................................................70
11.7
Handling of Missing Data ................................................................................71
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11.8
Multiplicity.......................................................................................................71
11.9
Safety................................................................................................................72
11.9.1
Treatment Exposure......................................................................................72
11.9.2
Medical History............................................................................................72
11.9.3
Concomitant Therapies.................................................................................72
11.9.4
Safety Parameters .........................................................................................72
11.9.5
Adverse Events.............................................................................................73
11.10
Interim Analyses...............................................................................................73
11.11
Sample Size Justification..................................................................................73
12
ADVERSE EVENTS............................................................................................74
12.1
General Information .........................................................................................74
12.2
Monitoring for Adverse Events ........................................................................74
12.3
Procedures for Recording and Reporting AEs and SAEs.................................75
12.4
Intensity and Causality Assessments................................................................78
12.5
Unmasking of the Study Treatment..................................................................79
12.6
Follow-Up of Subjects with Adverse Events....................................................79
12.7
Pregnancy in the Clinical Trial.........................................................................79
13
DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS ..................80
13.1
Completion of Source Documents and Electronic Case Report Forms ...........80
13.2
Data Review and Clarifications........................................................................81
13.3
Regulatory Documentation and Records Retention .........................................81
13.4
Quality Assurance and Quality Control............................................................81
13.5
Data Monitoring Committee.............................................................................82
14
REFERENCES .....................................................................................................82
15
APPENDIX...........................................................................................................84
List of Tables
Table 10-1
Prohibited Medication......................................................................................66
List of Figures
Figure 10-1
Dosing Schedule by Treatment........................................................................52
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5
INTRODUCTION
5.1
Study Rationale and Background
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
affecting 10%-13% of individuals over the age of 65 in North America, Europe, and Australia 
(Kawasaki 2010, Rein 2009, Smith 2001). Genetic, environmental and health factors play an 
important role in the pathogenesis of the disease. 
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or dry form and 
the neovascular (exudative) or wet form (Ferris 1984, Lim 2012, Miller 2013). Neovascular 
AMD is characterized by the growth of abnormal new blood vessels (neovascularization) 
under the retinal pigment epithelium (RPE) or subretinal space from the subjacent choroid, 
termed choroidal neovascularization (CNV) (Ferris, 1984). These newly formed vessels have 
an increased likelihood to leak blood and serum, damaging the retina by stimulating 
inflammation and scar tissue formation. This damage to the retina results in progressive, 
severe, and irreversible vision loss (Shah 2007, Shah 2009). Without treatment, most affected 
eyes will have poor central vision (20/200) within 12 months (TAP 2003). Although the 
neovascular form of the disease is only present in about 10% of all AMD cases, it accounted 
for approximately 90% of the severe vision loss from AMD prior to the introduction of anti-
vascular endothelial growth factor (VEGF) treatments (Ferris 1983, Sommer 1991, Wong 
2008).
VEGF has been shown to be elevated in patients with neovascular AMD and is thought to 
play a key role in the neovascularization process (Spilsbury 2000). The use of intravitreal 
(IVT) pharmacotherapy targeting VEGF has significantly improved visual outcomes in 
patients with neovascular AMD (Bloch 2012, Campbell 2012). Anti-VEGF treatments, such 
as ranibizumab (LUCENTIS®) and aflibercept (EYLEA®), inhibit VEGF signaling 
pathways and have been shown to halt the growth of neovascular lesions and resolve retinal 
edema.
Ranibizumab
In two Phase 3 studies of ranibizumab with monthly dosing regimens, approximately 95% of 
ranibizumab treated subjects experienced stabilization of vision (defined as a loss of fewer 
than 15 early treatment diabetic retinopathy study [ETDRS] letters) or improvement in vision 
at 12 months compared with 62% and 64% in the control groups (Rosenfeld 2006, Brown 
2009). Twenty-five to 40% of subjects in the ranibizumab groups gained ≥ 15 letters at 12 
months compared with 5-6% in the 2 control groups. On average, ranibizumab treated 
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subjects gained 7-11 letters of vision after 12 months, whereas control subjects lost an 
average of approximately 10 letters. This gain in visual acuity was essentially maintained 
during the second year of both Phase 3 studies while vision, on average, continued to decline 
in the control group. The visual acuity benefits, which indicate a suspension of neovascular 
AMD rather than a slowdown of its progression, were supported by corresponding effects on 
lesion anatomy and subject reported outcomes. The latter demonstrated statistically and 
clinically meaningful improvements in near activities, distance activities, and vision specific 
dependency as measured by the National Eye Institute Visual Function Questionnaire-25 
(VFQ-25).
Aflibercept
In two parallel Phase 3 trials of aflibercept, treatment naïve subjects with neovascular AMD 
were randomized to 2 doses (0.5 and 2.0 mg) and 2 regimens (every 4 weeks and every 8 
weeks with 2.0 mg) or the control arm (ranibizumab 0.5 mg every 4 weeks). At 52 weeks, all 
aflibercept groups, independent of doses and regimens, were noninferior to the ranibizumab 
group with equal stabilization of vision in 95% of eyes (Heier 2012). In the 2 mg aflibercept 
every 4 weeks group, there was a mean best-corrected visual acuity (BCVA) improvement of 
9.3 letters and in the 2 mg aflibercept every 8 weeks group there was an improvement of 8.4 
letters compared to the control group which had a mean improvement of 8.7 letters. In the 
second year of the study subjects were switched to a capped (treatment required at least every 
12 weeks) pro re nata (PRN) regimen. The proportion of subjects who maintained BCVA 
ranged between 91% and 92% for all groups. Mean BCVA improvements ranged from 7.9 
(ranibizumab), 7.6 (aflibercept 2 mg every 4 weeks and every 8 weeks) to 6.6 (aflibercept 0.5 
mg every 4 weeks). The retreatment frequency was similar between the aflibercept and 
ranibizumab arms during the capped PRN year, with a mean of 4.1 injections for the 
aflibercept 2 mg every 4 weeks arm, 4.2 injections for the aflibercept 2 mg every 8 weeks 
arm and 4.7 for the ranibizumab arm (Schmidt-Erfurth 2014).
RTH258
RTH258, formerly known as ESBA1008, is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of VEGF with a molecular weight of ~26 kDa that is being developed for 
the treatment of CNV associated with  neovascular AMD. It is an inhibitor of VEGF-A and 
works by binding to the receptor binding site of the VEGF-A molecule, thereby preventing 
the interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of 
endothelial cells. Increased levels of signaling through the VEGF pathway are associated 
with pathologic ocular angiogenesis and retinal edema. Inhibition of the VEGF pathway has 
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been shown to inhibit the growth of neovascular lesions and resolve retinal edema in patients 
with neovascular AMD.
In an ascending single dose study, Alcon protocol C-10-083, several doses of RTH258 (0.5, 
3.0, 4.5 and 6 mg), were evaluated versus ranibizumab 0.5 mg with regard to the mean 
change from Baseline to Month 1 in central subfield thickness (CSFT) as measured by 
spectral-domain optical coherence tomography (SD-OCT) (primary efficacy endpoint). 
Treatment with RTH258 provided similar reductions for all doses in CSFT to ranibizumab. 
The primary statistical analysis compared RTH258 4.5 mg and 6.0 mg versus ranibizumab 
0.5 mg with both doses achieving noninferiority. Notable however was the median time to 
receiving standard of care which was longer for the RTH258 3.0 mg, 4.5 mg and 6.0 mg 
doses (75 days in the 6.0 mg group compared with 45 days in the ranibizumab group), 
suggesting a longer duration of treatment effect. RTH258 6 mg was the highest dose tested in 
the study and no unexpected safety issues were reported that would preclude further clinical 
development.
Subsequently the safety and efficacy of the RTH258 6 mg dose were evaluated versus 
aflibercept 2 mg in a 56 week multiple dose study (Alcon protocol C-12-006) with a primary 
endpoint at 12 weeks. The efficacy data from this study showed that RTH258, when it was 
given every 8 weeks (q8), was as effective as the active control in terms of BCVA change 
from Baseline. There were numerical advantages with RTH258 over aflibercept with regard 
to the change in CSFT from Baseline. The majority (72%) of the RTH258 treated subjects 
who completed an extension of the study, who received treatment every 12 weeks (q12), 
showed visual stability. There were no adverse events in the RTH258 group that negatively 
differentiated the drug from the control. The majority of adverse events were mild or 
moderate in nature and either resolved spontaneously or with treatment.
5.1.1
Dose Rationale
C-10-083 and C-12-006 suggest that a 6 mg dose of RTH258 is effective and safe. The 
RTH258 3 mg dose is included in order to evaluate the dose-response relationship following 
multiple dosing with RTH258.
5.1.2
Treatment Regimen Rationale
While VEGF inhibitors have vastly improved patient outcomes for neovascular AMD, there 
still remains a need for treatments and regimens which offer a reduced frequency of 
injections. Frequent treatment and monitoring schedules remain a significant burden to 
patients, caregivers and physicians. The proposed Phase 3 study aims to address these.
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In the current study, RTH258 patients will receive q12 maintenance dosing. Disease activity 
assessments will be conducted by a masked investigator at Weeks 16, 20, 32 and 44, allowing 
four time points up to the primary endpoint of the study (Week 48) where RTH258 q12 
subjects can be reassigned to q8 treatment. It is expected that early determination at Week 16 
and Week 20 of subjects who are more suited to a q8 dosing regimen will minimize the 
percentage of q12 subjects who will require reassignment at later time points. Analyses from 
the PIER (Regillo 2008) and EXCITE (Schmidt-Erfurth 2011) studies have shown that visual 
and anatomic response during and for the 12 weeks after the loading phase are associated 
with visual acuity outcomes over the remainder of the first year of treatment. In addition, 
recent analyses from the EXCITE (Chong 2013) study have also shown that subjects who 
lose vision during the initial loading phase will have better visual outcomes with more 
frequent treatment versus q12 treatment. Finally, analyses from CATT (Kim 2014, Ying 
2014) and EXCITE (Simader 2014) have also shown that new intraretinal fluid 
(IRF)/intraretinal cysts (IRC), and to a lesser degree CSFT increase, are associated with later 
visual acuity decline.
5.2
Benefits and Potential Risks
RTH258 is an inhibitor of VEGF with a mechanism of action similar to ranibizumab but with 
a smaller molecular size (26 kDa and 48 kDa respectively).
Nonclinical studies have demonstrated that RTH258 is at least as potent as ranibizumab, with 
a similar vitreal half-life and a significantly lower systemic exposure. The low systemic 
exposure should confer a good safety profile even at a high dose. The higher dose, similar 
half-life, and potency of RTH258 may confer a longer treatment duration compared to 
currently available treatments. Two clinical studies, C-10-083 and C-12-006, have 
demonstrated that RTH258 is as effective as ranibizumab and aflibercept in improving BCVA 
outcomes whilst having a reduced treatment frequency, thus providing a potential benefit to 
patients and their caregivers/physicians. The ocular and systemic safety profile of single or 
repeated doses of RTH258 were also evaluated in the C-10-083 and C-12-006 studies, 
respectively, and demonstrated similar safety profiles to ranibizumab and aflibercept. Further 
details of the known and potential risks and benefits associated with RTH258 are presented in 
the Investigator’s Brochure.
Summarized, the results from the Phase 2 studies demonstrate that RTH258 has similar 
efficacy to currently available treatment options with potentially greater duration. These data 
support the further development of RTH258 with a treatment regimen including q12 
maintenance dosing.
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6
ETHICS
This clinical study will be conducted in accordance with the principles of the Declaration of 
Helsinki, and in compliance with the International Conference on Harmonization (ICH) E6 
Good Clinical Practice (GCP) Consolidated Guideline and other regulations as applicable. 
The Investigator and all clinical study staff will conduct the clinical study in compliance with 
the protocol. The Investigator will ensure that all personnel involved in the conduct of the 
study are qualified to perform their assigned responsibilities through relevant education, 
training, and experience.
Before clinical study initiation, this protocol, the informed consent form (ICF), any other 
written information given to subjects, and any advertisements planned for subject recruitment 
must be approved by an Independent Ethics Committee/Institutional Review Board 
(IEC/IRB). The Investigator must provide documentation of the IEC/IRB approval to the 
Sponsor. The approval must be dated and must identify the applicable protocol, amendments 
(if any), ICF, all applicable recruiting materials, written information for subject, and subject 
compensation programs. The IEC/IRB must be provided with a copy of the Investigator’s 
Brochure, any periodic safety updates, and all other information as required by local 
regulation and/or the IEC/IRB. At the end of the study, the Investigator will notify the 
IEC/IRB about the study’s completion. The IEC/IRB will also be notified if the study is 
terminated prematurely. Finally, the Investigator will report to the IEC/IRB on the progress of 
the study at intervals stipulated by the IEC/IRB.
Voluntary informed consent will be obtained from every subject (and/or legal representative, 
as applicable) prior to the initiation of any screening or other study related procedures. The 
Investigator must have a defined process for obtaining consent. Specifically, the Investigator, 
or designee, will explain the clinical study to each potential subject and the subject must 
indicate voluntary consent by signing and dating the approved ICF. The subject must be
provided an opportunity to ask questions of the Investigator, and if required by local 
regulation, other qualified personnel. The Investigator must provide the subject with a copy 
of the ICF written in a language the subject understands. The ICF must meet all applicable 
local laws and will provide subjects with information regarding the purpose, procedures, 
requirements, and restrictions of the study, along with any known risks and potential benefits 
associated with the investigational product, the available compensation, and the established 
provisions for maintaining confidentiality of personal, protected health information. Subjects 
will be told about the voluntary nature of participation in the study and will be provided with 
contact information for the appropriate individuals should questions or concerns arise during 
the study. The subject also will be told that their records may be accessed by appropriate 
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authorities and Sponsor designated personnel. The Investigator must keep the original, signed 
copy of the ICF and must provide a duplicate copy to each subject.
7
PROTOCOL AMENDMENTS
Modification of the protocol is prohibited without prior written agreement in the form of a 
protocol amendment. All amendments will be created by the Sponsor and must be approved 
by the IEC/IRB prior to implementation except when required to mitigate immediate safety 
risks or when the changes involve only logistical or administrative revisions.
Amendments may necessitate that the ICF and other study-related material be revised. If the 
ICF is revised, all subjects currently enrolled in the study may be required by the IEC/IRB to 
sign the approved, revised ICF.
8
SUBJECT POPULATION
The study population includes approximately 990 subjects to be randomized at approximately 
320 sites. To participate in the study, subjects must be ≥ 50 years of age with untreated active 
CNV secondary to AMD in the study eye. The expected duration of subject participation in 
the randomized portion of the study is 96 weeks. The complete inclusion and exclusion 
criteria are presented in Section 1.
9
TREATMENTS ADMINISTERED
At Visit 1/Baseline (Day 0), all eligible subjects will be randomized centrally using 
Interactive Response Technology (IRT) in a 1:1:1 ratio to receive either RTH258 3 mg/50 µL, 
RTH258 6 mg/50 µL, or aflibercept 2 mg/50 µL. Randomization for subjects in Japan will be 
stratified according to presence or not of polypoidal choroidal vasculopathy (PCV) identified 
using indocyanine green (ICG) imaging and confirmed by the Central Reading Center (CRC) 
at the screening visit.
In the event that IRT is not available for randomization, the site should contact the Sponsor 
about how to proceed. In these cases subjects may be manually randomized.
Throughout the study, the Investigator will be responsible for the accounting of all study 
materials and investigational products, and will ensure that the investigational products are 
not used in any unauthorized manner.
9.1
Identity of Study Treatments
Test Article: 
RTH258 solution for IVT injection, 3 mg in 50 µL and 6 mg in 50 µL
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Control Article: 
Aflibercept solution for IVT injection, 2 mg in 50 µL
The RTH258 trial kits will consist of a carton that contains 1 single use, sterile glass vial 
containing RTH258.
The availability of the control article, as well as regional regulatory requirements, will 
determine aflibercept sourcing. Some sites will be supplied with aflibercept by the Sponsor 
and others may be requested to utilize vials from their own stock.
Sponsor supplied: The aflibercept trial kits consist of a masked, numbered carton containing 
one commercially labeled vial of aflibercept.
Site supplied: Aflibercept will be obtained by the site in its original package. In these cases 
masked, numbered, empty kits will be supplied that contain instructions to administer an 
aflibercept injection. The lot number and expiry date of the aflibercept will be recorded.
Kit labels on all trial kits will include the kit number, protocol number, storage conditions, 
and a statement that the product is for investigational use only.
All trial kits should be stored at 2º to 8ºC (35.6º to 46.4ºF); do not freeze. To ensure proper 
conditions are maintained, a daily (7 days/week) temperature log will be maintained 
documenting appropriate investigational product storage conditions.
9.2
Usage
RTH258 3 mg and RTH258 6 mg will be administered by IVT injection. All doses will be 
delivered in 50 µL (0.05 mL). Both treatment groups will receive 3 loading doses of their 
respective treatment at Visit 1/Day 0, Visit 2/Week 4 and Visit 3/Week 8. After the loading 
doses subjects will receive q12 treatment unless there is disease activity according to the 
guidance provided in Section 10.1. If disease activity is identified, the subject will be 
reassigned to receive injections q8 thereafter up to Visit 25/Week 92.
Aflibercept will be administered as a 2 mg dose in a 50 µL (0.05 mL) injection. Subjects 
randomized to receive aflibercept will receive 3 loading doses at Visit 1/Day 0, Visit 2/Week 
4 and Visit 3/Week 8 followed by injections at q8 intervals up to Visit 25/Week 92.
To maintain masking, beginning at Visit 6/Week 16, if a subject does not receive an active 
injection, they will receive a sham injection.
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If at any visit, including Baseline, a subject is accidentally treated with investigational 
product (IP) from an arm other than the one to which they were assigned, they will be treated 
with the IP to which they were randomized to and according to the treatment schedule of that 
arm for the remainder of the study. Any instance of this must be reported to the Sponsor 
immediately.
9.3
Accountability Procedures
Each site must have designated unmasked site personnel who, upon receipt of the IP, will 
conduct an inventory. At the appropriate study visits, designated unmasked study staff will 
provide the IP to the unmasked injecting physician in accordance with the IRT procedures.
During the study, the Investigator must maintain records of IP dispensation and collection for 
each subject. This record must be made available to the unmasked study monitor for the 
purposes of verifying the accounting of clinical supplies. Any discrepancies and/or 
deficiencies between the observed disposition and the written account must be recorded along 
with an explanation. At the conclusion of the study, the Investigator will be responsible for 
returning all used and unused study supplies unless otherwise instructed by the Sponsor.
9.4
Subject Confidentiality and Methods Used to Minimize Bias
The Investigator must ensure that the subject’s anonymity is maintained throughout the 
course of the study. In particular, the Investigator must keep an enrollment log with 
confidential identifying information that corresponds to the subject number of each study 
participant. At the end of the clinical study, the Sponsor will collect a copy of the enrollment 
log without any identifying subject information. All documents submitted to the Sponsor will 
identify the subject exclusively by number and demographic information. No other 
personally identifying information should be transmitted to the Sponsor.
The intent of masking is to limit the occurrence of conscious and unconscious bias in the 
conduct and interpretation of the clinical study. Bias could arise from the influence that the 
knowledge of a specific treatment assignment may have on the recruitment and allocation of 
subjects, their subsequent care, the assessment of end points, the handling of withdrawals, 
and so on. The essential aim of masking, therefore, is to prevent identification of the 
treatments by the Investigator, subject, and others associated with the conduct of the study 
until all such opportunities for bias have passed.
This study will be double-masked, with subjects randomized to be treated with RTH258 3 
mg, RTH258 6 mg or aflibercept 2 mg. All members of the Clinical Study Team will be 
masked to treatment assignments while the study is in progress. In addition, the biostatistician
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who is directly involved in the conduct of the study (i.e. involved in patient level discussions 
or direct interaction with sites) will remain masked to treatment assignments while the study 
is in progress. Sponsor personnel who have access to treatment codes (eg, SAS® 
Programming, personnel directly involved with bioanalysis of serum samples, unmasked 
monitors performing IP accountability, and Clinical Supplies personnel) will not divulge the 
codes to subjects, Investigators, site staff, Sponsor Clinical Trial Management (CTM), or 
Sponsor Clinical Site Management (CSM). If necessary, the Sponsor may be required to 
unmask a subject if an adverse event (AE) meets criteria of a Suspected Unexpected Serious 
Adverse Reaction (SUSAR) in order to fulfill expedited regulatory reporting requirements. In 
this event, the Sponsor Safety Review Team will not divulge the treatment code to any other 
personnel involved in reporting, obtaining, and/or reviewing the clinical evaluations. This 
level of masking will be maintained throughout the conduct of the study.
Each site must have both masked and unmasked physicians available. The physician who 
performs the injection will be unmasked to the treatments as will any other site personnel 
who have been delegated responsibility for working with the IP. The unmasked site personnel 
and unmasked injecting physician must not perform BCVA, complete ophthalmic 
examination, disease activity assessments or administer the VFQ-25. Also, the unmasked site 
personnel and unmasked injecting physician must not perform assessment of any ocular or 
nonocular safety parameters, or assess causality AEs for subjects during the course of the 
study except an event reported immediately following IVT injection. The unmasked 
physician/site personnel should, however, assess subject safety immediately following 
injection (ie, they will perform the postinjection assessment; the masked physician/site 
personnel should not perform this assessment). Unmasked monitors will be provided to 
perform IP accountability.
Treatment will be assigned to subjects through the IRT system. Each subject number will be 
associated with treatment groups according to a random process. Subjects will be assigned 
treatment in numerical order; the randomization schedule will be blocked to ensure a balance 
of treatment allocations across the study. The IRT system will be utilized to implement the 
outcome of the disease activity assessments at the appropriate visits.
The randomization scheme will be generated and maintained by the Sponsor. Once all study 
data have been verified, validated, and the database locked, individual subjects will be 
unmasked to their treatment. In the event of a medical emergency during the study where the 
knowledge of subject treatment is required, an individual Principal Investigator will have the 
ability to unmask the treatment assignment for a specific subject. The Investigator should 
notify the Sponsor prior to unmasking a subject, if there is sufficient time. Further, the 
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Sponsor must be informed whenever the randomization code is broken and the reasons for 
unmasking.
10
STUDY PROCEDURES
10.1
Outline of Study
This is a prospective, randomized, double masked, multicenter, 3 arm study. Subjects with 
untreated active CNV secondary to AMD who meet all inclusion/exclusion criteria will be 
included in the study. The study will be conducted at approximately 320 sites and will 
randomize approximately 990 subjects.
The Investigator or a designee is responsible for scheduling study visits and ensuring subject 
compliance with the visit schedule. Subjects missing a scheduled visit should be contacted 
immediately to reschedule the examination, preferably within the specified study visit period.
SD-OCT imaging, fluorescein angiography (FA) and color fundus photography will be 
performed at the Screening Visit and the images will be assessed by CRC. In Japan, ICG will 
also be performed and the images will be assessed by the CRC. The CRC will review these 
images to confirm subject eligibility based upon the lesion attributes specified in the 
inclusion/exclusion criteria. Subjects who meet all inclusion and no exclusion criteria, and 
are confirmed as eligible by the CRC will return to the site for the Visit 1/Baseline (Day 0).
At the Visit 1/Baseline, subjects will be randomized to 1 of 3 arms in a 1:1:1 ratio per the 
randomization schedule.
Arms 1 and 2 (RTH258):
Subjects randomized to RTH258 3 mg (Arm 1) and RTH258 6 mg (Arm 2) will be initially 
injected at 4 week intervals, at Visit 1/Day 0, Visit 2/Week 4 and Visit 3/Week 8.
Following these loading doses, each subject will be injected q12 up to Week 92 unless there 
is disease activity according to the guidance provided at Visit 6/Week 16, Visit 7/Week 20, 
Visit 10/Week 32, Visit 13/Week 44, Visit 16/Week 56, Visit 19/Week 68 or Visit 22/Week 80. 
If disease activity is identified, the subject will be reassigned to receive injections q8 
thereafter, up to Week 92. The IRT system will make the necessary changes to the dosing per 
the masked Investigator’s assessment. The disease activity assessment will also be performed 
at Visit 25/Week 92 but will not be entered into IRT and will have no effect on the subject’s 
treatment regimen.
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Page 53 of 84
screening.
2. Obtain demographic information and medical history, including information on all 
medications used within the past 90 days. 
3. Perform a general physical exam.
4. Collect vital signs (blood pressure and pulse).
5. Perform a pregnancy test if the subject is female and of childbearing potential. 
6. Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
forward the samples to the central laboratory. Blood draws should be performed prior 
to injection of fluorescein dye.
7. Perform BCVA on both eyes. 
8. Perform a complete ophthalmic examination on both eyes including slit-lamp exam, 
intraocular pressure (IOP) measurement and fundus exam.
9. Perform SD-OCT on both eyes. Submit the images (within 24 hours, if possible) to 
the CRC for determination of eligibility.
10. Perform FA on both eyes. Submit the images (within 24 hours, if possible) to the 
CRC for determination of eligibility.
11. Perform 3-field color fundus photography on both eyes. Submit the images (within 24 
hours, if possible) to the CRC for determination of eligibility.
12. At Japanese sites: Perform ICG imaging on both eyes. Submit the images (within 24 
hours, if possible) to the CRC for AMD subtype analysis.  
13. Register the subject (including screen fails) in the Electronic Data Capture (EDC) 
system and obtain a subject ID number.
14. Contact IRT to enter the subject ID number.
15. Monitor for AEs.
16. Schedule Visit 1/Baseline to take place 2 to 14 days after the start of the Screening 
assessments.
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10.2.2
Visit 1/Baseline (Day 0)
At the Baseline Visit, subjects will be randomized only if the subject has successfully met all 
of the eligibility criteria.
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Record any AEs that are observed or reported, including those associated with 
changes in concomitant medication dosing. 
3. Administer the VFQ-25, using validated translations as applicable and available. The 
VFQ-25 should be administered prior to any examination.
4. Collect vital signs (blood pressure and pulse).
5. Obtain a blood sample for anti-drug antibody (ADA) analysis. Blood draws should 
take place prior to the IVT injection.
6. Obtain a blood sample for systemic RTH258 analysis. Blood draws should take place 
prior to the IVT injection.
7. Perform BCVA on both eyes. Baseline BCVA of the study eye must be between 78 
and 23 letters, inclusive, for the subject to qualify.
8. Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement, and fundus exam (dilation to be performed at the discretion 
of the Investigator). 
9. Perform SD-OCT imaging on the study eye and submit the images to the CRC. 
10. Where applicable, perform fundus autofluorescence (FAF) imaging on the study eye
and submit the images to the CRC. FAF will only be performed at a subset of sites.
11. Verify that all eligibility criteria have been met, including the required screening 
imaging eligibility from the CRC. The Investigator should also review the results 
from the central laboratory for the samples collected at Screening to determine if 
there is anything that would preclude participation of the subject.
12. Contact IRT to obtain a kit number. 
13. Have the unmasked Investigator perform an IVT injection according to the 
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randomization/kit assignment. The injection procedure may be performed at a 
later time, as long as it occurs within 7 days of the scheduled visit.
14. After the injection, perform a postinjection assessment of the study eye 0-5 minutes 
and at 30 (± 15) minutes after injection (and at further time points, as needed).  
15. Schedule Visit 2/Week 4 to take place 28 ± 3 days after Visit 1/Baseline.
10.2.3
Visit 2/Week 4 (Day 28 ± 3 Days) and Visit 3/Week 8 (Day 56 
± 3 Days)
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Record any AEs that are observed or reported, including those associated with 
changes in concomitant medication dosing. 
3. Collect vital signs (blood pressure and pulse).
4. Obtain a blood sample for ADA analysis (Visit 2 only). Blood draws should take 
place prior to the IVT injection.
5. Obtain a blood sample for systemic RTH258 analysis (Visit 2 only). Blood draws 
should take place prior to the IVT injection. 
6. Perform BCVA on the study eye.
7. Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement, and fundus exam (dilation to be performed at the discretion 
of the Investigator). 
8. Perform SD-OCT imaging on the study eye and submit the images to the CRC.
9. Contact IRT to obtain a kit number. 
10. Have the unmasked Investigator perform an IVT injection according to the 
randomization/kit assignment. The injection procedure may be performed at a 
later time, as long as it occurs within 7 days of the scheduled visit and is within 
the visit window.
11. After the injection perform a postinjection assessment of the study eye 0-5 minutes 
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and at 30 (± 15) minutes after injection (and at further time points, as needed).
12. Schedule Visit 5/Week 12 to take place 84 ± 7 days after Visit 1/Baseline.
10.2.4
Visit 4 (Visit 3 + 1 Day)
This visit only applies to the subset of subjects who were randomly selected to attend it and 
did so before Version 3.0 of the protocol became effective.
10.2.5
Visit 5 /Week 12 (Day 84 ± 7 Days) Through Visit 25 /Week 92 
(Day 644 ± 7 Days)
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Record any AEs that are observed or reported, including those associated with 
changes in concomitant medication dosing. 
3. Administer the VFQ-25, using validated translations as applicable and available (Visit 
8, Visit 14 and Visit 20 only). The VFQ-25 should be administered prior to any 
examination.
4. Perform a general physical exam. (Visit 14 only).
5. Collect vital signs (blood pressure and pulse).
6. Perform a pregnancy test if the subject is female and of childbearing potential (Visit 
14 only).
7. Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
forward the samples to the central laboratory (Visit 5 and Visit 14 only). Blood draws 
should be performed prior to any IVT or sham injection and prior to injection of 
fluorescein dye.
8. Obtain a blood sample for ADA analysis (Visit 5, Visit 8, Visit 11, Visit 14, Visit 19, 
Visit 24 only). Blood draws should be performed prior to any IVT or sham injection 
and prior to any injection of fluorescein dye.
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9. Obtain a blood sample for systemic RTH258 analysis (Visit 5, Visit 8, Visit 11, Visit 
14, Visit 19, Visit 24 only). Blood draws should be performed prior to any IVT or 
sham injection and prior to any injection of fluorescein dye.
10. Perform BCVA on the study eye. 
Perform BCVA on both eyes (Visit 5, Visit 8, Visit 11, Visit 14, Visit 17, Visit 20 and 
Visit 23 only).
11. Perform a complete ophthalmic examination on the study eye including slit-lamp 
exam, IOP measurement and fundus exam (dilation to be performed at the discretion 
of the Investigator). 
Perform a complete ophthalmic exam on both eyes (Visit 14 only). 
12. Perform SD-OCT on the study eye and submit the images to the CRC. 
Perform SD-OCT on both eyes and submit the images to the CRC (Visit 14 only).
13. Perform FA (study eye only at Visit 5, both eyes at Visit 14) and submit the images 
to the CRC (Visit 5 and Visit 14 only).
14. Perform color fundus photography (study eye only at Visit 5, both eyes at Visit 14) 
and submit the images to the CRC (Visit 5 and Visit 14 only).
15. Where applicable, perform FAF imaging on the study eye and submit the images to 
the CRC (Visit 5 and Visit 14 only). FAF will only be performed at a subset of sites.
16. Have the masked Investigator perform the visit appropriate disease activity 
assessment for the study eye (Visit 6, Visit 7, Visit 10, Visit 13, Visit 16, Visit 19, 
Visit 22 and Visit 25 only).
17. Contact IRT (all visits except Visit 5). 
18. Have the unmasked Investigator perform an IVT or sham injection according to the 
randomization/kit assignment (all visits except Visit 5). The injection procedure 
may be performed at a later time, as long as it occurs within 7 days of the 
scheduled visit and is within the visit window.
19. After injection perform a postinjection assessment of the study eye 0-5 minutes and 
at 30 (± 15) minutes (and at further time points, as needed) (all visits except Visit 5).
20. Schedule Visit 26/Week 96 to take place 672 ± 7 days after Visit 1/Baseline.
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10.2.6
Visit 26/Week 96/Exit Visit (Day 672 ± 7 Days) or Early Exit
1. Obtain information on any changes in medical health and/or the use of concomitant 
medications.
2. Record any AEs that are observed or reported, including those associated with 
changes in concomitant medication dosing. 
3. Administer the VFQ-25, using validated translations as applicable and available. The 
VFQ-25 should be administered prior to any examination.
4. Perform a general physical exam.
5. Collect vital signs (blood pressure and pulse).
6. Perform a pregnancy test if the subject is female and of childbearing potential. 
7. Obtain blood and urine samples for blood chemistry/hematology and urinalysis and 
forward the samples to the central laboratory. Blood draws should be performed prior 
to injection of fluorescein dye.
8. Obtain a blood sample for ADA analysis (if the subject exits at or before Visit 24).
Blood draws should be performed prior to injection of fluorescein dye.
9. Obtain a blood sample for systemic RTH258 analysis (if the subject exits at or before 
Visit 24). Blood draws should be performed prior to injection of fluorescein dye.
10. Perform BCVA on both eyes.
11. Perform a complete ophthalmic examination on both eyes including slit-lamp exam, 
IOP measurement and fundus exam (dilation to be performed at the discretion of the 
Investigator).
12. Perform SD-OCT imaging on both eyes and submit the images to the CRC.  
13. Perform FA on both eyes and submit the images to the CRC. 
14. Perform color fundus photography on both eyes and submit images to the CRC. 
15. Where applicable, perform FAF on the study eye and submit the images to the CRC. 
FAF will only be performed at a subset of sites.
16. Complete the Exit Form.
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10.3
Unscheduled Visits
If a subject returns to the site prior to their next scheduled study visit for assessment of an 
adverse event, the Unscheduled Visit pages of the electronic case report form (CRF) should 
be completed. Procedures conducted at the Unscheduled Visit are at the discretion of the 
Investigator apart from treatments of the study eye for AMD. If the subject is discontinuing at 
the Unscheduled Visit, the CRFs for the Exit Visit should be completed rather than the CRFs 
for an Unscheduled Visit. Routine treatments and routine follow-up of the nonstudy eye will 
not be considered an Unscheduled Visit. Any treatments of the nonstudy eye will be captured 
on the Concomitant Medication Page.
10.4
Discontinued Subjects
Discontinued subjects are those who are lost to follow-up, withdraw or are withdrawn from 
the study after the Visit 1/Baseline. Subjects may discontinue from the study at any time for 
any reason. Discontinued subjects will not be replaced (ie, their subject numbers will not be 
re-assigned/re-used). The site must contact IRT to register the subject’s discontinuation from 
IP.
Should a subject exhibit any clinically relevant signs, symptoms, or other clinical 
observations that possibly could be associated with suspected sensitivity or intolerance to one 
of the study treatments, the Investigator must document those observations on an AE Form 
(AEF). If a subject discontinues the study with an ongoing AE, follow-up procedures, as 
appropriate and outlined in Section 12.6, should be performed.
Any subject who exits early from the study must undergo all procedures outlined at Visit 
26/Week 96 (Section 10.2.6). Additionally, the Exit Form must be completed and a reason for 
discontinuation must be identified.
If a subject exits early from the study between visits, the Investigator must attempt to contact 
the subject and request the subject to return for a final visit to complete the exit procedures. If 
the subject is unable or unwilling to return for the Exit Visit, the subject will be considered 
lost to follow-up and the ‘date of exit’ will be the date that the subject was last seen at the site 
or contacted by other communication.
Finally, to ensure the safety of all subjects who exit early from the study, Investigators should 
assess each subject and, if necessary, advise them of any therapies and/or medical procedures 
that might be needed to maintain their health.
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Page 64 of 84
AMD subtype which will be provided following expedited review and will be utilized by IRT 
in the randomization process.
10.7.12
Fundus Autofluorescence
FAF will be performed at a subset of sites in order to assess the occurrence of geographic 
atrophy. A standardized procedure for the collection of FAF images is provided by the CRC 
in a separate hand book. Certification of the equipment and examiners at each investigative 
site will occur prior to evaluation of study subjects. FAF will not be used to determine 
eligibility, but will be included beginning at the Visit 1/Baseline.
10.7.13
Disease Activity Assessment
The masked Investigator will assess the study eye of all subjects at Visit 6/Week 16, Visit 
7/Week 20, Visit 10/Week 32, Visit 13/Week 44, Visit 16/Week 56, Visit 19/Week 68 and 
Visit 22/Week 80. The IRT system will make the necessary changes to the dosing per the 
masked Investigator’s assessment. The disease activity assessment will also be performed at 
Visit 25/Week 92, but will not be entered into IRT and will have no effect on the subject’s 
treatment regimen. Details of the disease activity assessments are further outlined in the 
MOP.
10.7.14
Intravitreal Administration of Investigational Product
The IVT injection procedure for both the test article and control article is the same as that 
described for aflibercept in the product information sheet. IVT injection is contraindicated in 
subjects with active ocular or periocular infections and in subjects with active intraocular 
inflammation; therefore, the Investigator should verify that these conditions are not present in 
either eye (study and nonstudy eyes) prior to every injection. Specific instructions for 
injection procedures are provided in the MOP.
10.7.15
Administration of Sham Injection
Beginning at Visit 6/Week 16, at visits when subjects do not receive an active injection, they 
will be administered a sham injection. For the sham injection the tip of an injection syringe 
(the hub without a needle) will be used. A standardized procedure for the sham is described in 
the MOP.
10.7.16
Postinjection Assessment
The study eye will be assessed before, immediately (0-5 minutes) after and 30 (± 15) minutes 
after each IVT/sham injection to ensure that the procedure and/or the study medication have 
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not endangered the health of the eye. The postinjection assessments include an evaluation of 
central retinal artery perfusion via a gross assessment of vision (e.g.count fingers) and 
measurement of IOP according to the schedule detailed in the MOP. Direct visualization to 
assess the central retinal artery, presence of retinal detachment, presence of new intraocular 
hemorrhage(s) might be appropriate at the discretion of the investigator and/or based on the 
results of gross assessment of vision and IOP measurement. Assessments will continue until 
the central retinal artery is adequately perfused and the IOP is within 10 mmHg of the 
pre-injection value and is stable in the opinion of the Investigator. Any subject who 
develops significantly raised IOP (> 30 mmHg) or a non-adequately perfused central retinal
artery at any time during the study should be monitored according to the Investigator’s 
clinical judgment and may undergo additional procedures and measurements of IOP beyond 
those specified in the protocol. If, at the conclusion of the required evaluation period 
following an injection/sham, there are no safety concerns, the subject will leave the site. If 
any concern or immediate toxicity is noted, the subject will remain at the site and will be 
treated according to the designated evaluating physician’s clinical judgment. If any issues 
regarding IOP were noted during the postinjection assessment, then the subject should be 
scheduled for a follow-up visit (Unscheduled Visit) the day following injection/sham, if 
required in the opinion of the Investigator. Clinically relevant changes that are observed 
during the postinjection assessment should be reported as adverse events.
10.8
Concomitant Treatment
The Investigator should instruct the subject to notify the study site about any new 
medications he/she takes after enrolling into the study. 
Should the nonstudy eye require treatment during the study with an anti-VEGF, a drug which 
is approved for the treatment of exudative AMD in the respective country should be applied 
at the discretion of the Investigator and following the procedures established at the respective 
site. The nonstudy eye treatment may occur at any time once the Baseline study eye injection 
has been administered.
10.9
Prohibited Treatment
Use of treatments, as displayed in Table 10-1, are not allowed after the start of the study i.e., 
Screening. In addition, there are certain washout periods to be respected as outlined in the 
exclusion criteria.
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Table 10-1
Prohibited Medication
Medication
Study eye: Intra- or periocular corticosteroids
Study eye: Laser treatment for AMD
Study eye: Anti-VEGF therapy other than IP
Nonstudy eye: Unapproved or investigational treatment
Systemic: Systemic corticosteroids for 30 or more consecutive days (low stable doses of 
corticosteroids [defined as ≤10 mg prednisolone or equivalent dose], inhaled, nasal or 
dermal steroids are permitted)
Systemic: Anti-VEGF therapy
Any investigational drug, biologic or device (with the exception of  over-the-counter 
vitamins, supplements or diets)
11
ANALYSIS PLAN
11.1
General Considerations
Continuous variables will be summarized for the measured values and change from Baseline 
values using the number of observations, mean, standard deviation, median, quartiles, 
minimum and maximum. Categorical variables will be summarized with numbers and 
percent from each category. Treatment differences will be presented together with 95% 
confidence intervals as appropriate. 
11.2
Subject Evaluability
Subject evaluability based on pre-specified deviations and their impact on analysis sets will 
be determined prior to breaking the masked treatment assignment code and locking the 
database for the primary analysis at Week 48. Protocol deviations and their impact on 
analysis sets will be pre-specified in the deviations and evaluability plan (DEP).
11.3
Analysis Sets
The following analysis sets are defined:
All-enrolled analysis set: includes all subjects who signed an ICF and are assigned subject 
numbers. This analysis set will be used to summarize subject disposition and pre-treatment 
adverse events.
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All-randomized analysis set: includes all subjects who were randomized. This analysis set 
will be used to describe the randomized study population based on demographics and 
baseline characteristics.
Safety analysis set: includes all subjects who received at least one IVT injection. Subjects in 
the safety analysis set will be analyzed according to the first treatment received. This analysis 
set will be used for all safety analyses.
Full analysis set (FAS): includes all subjects who are randomized and received at least one 
IVT injection. Following the intent-to-treat (ITT) principle, subjects in the FAS will be 
analyzed according to the treatment group they are assigned at randomization. The FAS will 
be the primary analysis set for efficacy analyses.
The per protocol analysis set (PPS): defined for the primary and key secondary efficacy 
analysis at Week 48 includes all subjects in the FAS with no protocol deviations that are 
expected to majorly affect the assessment of efficacy at Week 48 including: lack of 
compliance (including treatment misallocation), missing data, concomitant medication and 
deviation from inclusion/exclusion criteria. Discontinuation from treatment due to lack of 
efficacy does not constitute a reason for exclusion from the PPS.Before the Week 48 database 
lock the relevant protocol deviations will be specified in the DEP document and identified at 
the subject level in the database.
11.4
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized for all analysis sets. All 
summaries will be presented by treatment group and overall.
11.4.1
Demographic Characteristics
The demographic parameters are age category (50 to 64, 65 to 74, 75 to 84, and ≥ 85), 
gender, ethnicity and race. Age will also be summarized as a continuous variable.
11.4.2
Baseline Characteristics
Baseline characteristics will include: primary diagnosis of neovascular AMD, time since 
diagnosis of neovascular AMD (days), whether neovascular AMD is unilateral or bilateral, 
BCVA (both as a continuous variable and using categories (≤ 55, 56-70, ≥ 71 letters), lesion 
type (predominantly classic, minimally classic, pure occult), foveal involvement (subfoveal, 
extrafoveal, undeterminable), CNV lesion size, presence of subretinal fluid, presence of 
intraretinal fluid/cyst, presence of sub RPE fluid, neurosensory retinal thickness, CSFT (both 
as a continuous variable and using categories (< 400 ≥ 400 µm).
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07-Aug-2017

 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
   
 
  
  
   
   
 
 
  
     
 
 
  
   
 
  
      
 
 
  
  
  
 
   
 
  
 
 
 
  
   
 
  
      
 
   
 
 
  
 
    
 
 
 
  
 
 
 
  
 
 
 
   
  
 
  
   
  
 
 
   
  
  
 
 
 
 
 
   
 
  
 
 
 
   
 
  
       
   
  
  
 
 
 
 
 
  
   
 
 
 
  
 
 
 
 
 
 
   
 
 
 
   
 
 
   
 
 
 
  
   
 
 
  
 
 
  
 
  
   
  
 
 
  
   
 
 
  
 
  
 
  
  
 
   
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  

 
 
 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
  
 
 
 
  
 
  
 
 
    
  
 
 
 
   
 
 
  
 
  
  
 
 
 
 
 
 
 
   
   
   
     
  
 
  
  
 
  
 
   
 
 
 
   
 
 
 
 
  
 
 
 
 
  
 
  
 
  
    
 
 
 
  
 
 
 
 
 
 
 
   
  
 
 
 
 
  
 
  
 
  
  
 
  
 
  
    
   
  
  
   
   
 
  
 
  
 
  
      
 
  
  
  
   
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
   
 
   
  
 
 
  
  
  
    
   
  
  
 
  
 
  
   
  
 
  
  
  
  
 
 
  
 
   
 
  
 
  
  
 
  
   
  
 
  
      

 
 
 
 
  
  
   
 
 
 
 
  
 
 
   
 
 
 
  
 
 
  
 
  
    
 
 
 
 
 
  
  
   
  
  
 
 
 
 
  
 
 
  
   
 
    
  
 
 
   
 
 
 
 
 
 
 
 
  
   
   
 
 
 
   
  
 
 
  
 
 
   
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
   
 
 
  
 
 
 
  
 
   
 
  
  
 
  
 
 
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
  
 
 

 
 
 
 
  
   
 
  
      
 
 
  
  
  
    
 
  
 
 
 
  
   
 
  
      
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
    
  
 
  
 
 
  
 
  
 
 
   
 
  
 
 
 
 
  
        
  
 
 
 
  
 
 
 
  
     
 
   
  
   
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
  
   
  
 
 
  
   
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
   
   
 
  
  
 
  
 
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
   
  
  
 
 
   
 
 
  
   
 
 
 
  
 
 
 
 
   
 
 
 
   
 
   
 
 

 
 
 
  
   
   
 
 
 
  
 
  
 
  
 
  
 
   
 
 
 
 
 
 
  
 
 
  
 
   
 
  
 
 
  
 
  
  
   
 
 
 
 
 
 
  
 
  
  
 
 
  
 
   
 
 
 
 
  
  
  
 
 
 
  
  
 
 
 
 
  
  
 
 
   
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
  
 
 
 
 
 
  
 
   
  
  
 
  
     
  
 
 
 
  
 
  
 
   
   
   
 
 
 
 
  
  
  
 
 
 
  
 
   
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
  
   
  
 
 
 
  
  
 
  
 
  
 
 
 
  
  
 
 
  
 
   
  
  
   
  
 
  
 
  
  
  
 
  
  
 
 
  
 
   
   
 
   
 
 
   
  
 
  
 
 
 
  
 
  
  
  
 
 
  
  
 
  
 
 
 
 
   
 
 
 
 
  
 
 
 
  
  
  
 
  
   
 
   
 
  
 
 
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
  
  
 
 
   
  
  
  
 
   
 
   
 

Page 74 of 84
change from Baseline to Week 48 at a two-sided alpha level of 0.05 with a power of 
approximately 90% assuming equal efficacy and a common standard deviation of 15 letters. 
A power of at least 90% can be expected for the first key secondary endpoint assuming that 
averaging over the 4 time points will not lead to an increase in the standard deviation.
To account for a drop-out rate of 10%, a total of 330 subjects will be randomized per 
treatment arm.
12
ADVERSE EVENTS
12.1
General Information
An AE is any untoward medical occurrence in a subject who is administered a study 
treatment regardless of whether or not the event has a causal relationship with the treatment. 
An AE, therefore, can be any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the study treatment,
whether or not related to the treatment. In clinical studies, any AE can include an untoward 
medical occurrence occurring at any time, including run-in or washout periods, even if no 
study treatment has been administered. The determination of clinical relevance is based upon 
the medical judgment of the Investigator.
12.2
Monitoring for Adverse Events
At each visit, after the subject has had the opportunity to spontaneously mention any 
problems, the Investigator should inquire about AEs by asking the standard questions:
•   “Have you had any health problems since your last study visit?”
•   “Have there been any changes in the medicines you take since your last study visit?”
AEs should be reported for any clinically relevant change in concomitant medication(s) that 
is the result of an untoward (unfavorable and unintended) change in a subject's medical 
health.  
Changes in any protocol-specific parameters and questionnaires (if applicable) evaluated 
during the study are to be reviewed by the Investigator. Any untoward (unfavorable and 
unintended) change in a protocol-specific parameter or questionnaire response that is 
clinically relevant is to be reported as an AE. These clinically relevant changes will be 
reported regardless of causality.
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TDOC-0050793
Protocol - Clinical
07-Aug-2017

 
 
  
 
 
 
 
 
  
  
  
 
 
  
 
  
 
  
 
  
   
 
 
 
 
 
  
 
  
 
 
 
  
   
 
  
 
 
   
 
 
  
 
 
 
 
  
  
 
  
  
 
 
 
 
   
   
   
   
 
 
   
 
 
 
 
   
  
 
 
   
 
 
  
 
 
 
 
 
 
    
 
  
 
 
  
  
 
   
 
  
 
 
  
 
  
   
  
   
 
 
 
 
 
 
  
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
  
 
 
  
    
 
 
  
 
 
 
 
 
  
 
  
   
 
 
 
   
   
  
  
 
 
 
 
 
 
   
   
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
   
  
 
  
 
 
 
 
  
 
 
 
  
 
 
   
 
   
 
 
 
 
 
 
  
   
 
 
  
  
 
 
  
  

 
 
 
  
   
 
 
  
 
  
 
  
  
 
 
  
   
 
   
 
  
 
  
 
 
 
 
 
  
 
   
 
  
 
  
 
 
   
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
    
  
 
  
 
 
  
 
 
  
 
 
   
  
  
  
  
  
 
  
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
    
 
 
  
  
 
  
 
 
 
 
 
 
 
 
   
 
   
 
 
  
    
  
 
   
  
 
  
 
 
 
   
 
 
 
 
 
 
   
 
  
   
 
  
  
   
  
 
   
  
 
 
 
  
 
   
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
   
  
  

 
 
 
  
 
 
    
  
   
 
  
   
 
   
 
 
  
 
  
   
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
    
   
  
   
 
 
  
 
   
 
 
  
  
 
  
  
  
 
   
  
  
   
 
 
  
  
 
 
 
  
   
  
 
 
 
  
 
   
 
 
 
 
  
 
 
  
   
 
   
 
 
  
 
   
 
 
   
 
 
 
   
 
 
   
 
  
 
 
  
 
  
 
   
  
   
  
 
  
   
  
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
  
 
  
 
 
   
 
 
  
 
 
 
  
  
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
    
  
 
 
  
 
 
  
 
 
 
  
 
  
 
   
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
  
  
 
  
   
 
 
   
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
    
 
  
  
    
 
  
   
   
 
 
  
 
 
  
 
  
 
 
 
 
 
   
 
  
 
   
 
   
 
  
 
 
  
 
 
 
  
 
   
 
 
   
  
  
 
  
   
   
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
  
 
  
 
 
 
 
 
  
  
  
 
  
  
  
 
  
 
  
  
   
 
 
 
  
   
 
   
   
  
    
 
  
 
 
   
   
  
 
  
 
 
  
 
 
  
 
 
   
   
  
  
  
   
 
  
  
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
      
 
  
 
 
 
  
 
 
  
 
 
  

Page 79 of 84
direct cause and effect relationship between the study treatment and the 
AE has not been demonstrated but there is a reasonable possibility that the 
AE was caused by the study treatment.
Not Related
An AE considered unrelated to the use of the study treatment. AEs 
classified as not related may either be definitely unrelated or simply 
unlikely to be related (ie, there are other more likely causes for the AE).
An assessment of causality will also be performed, when appropriate, by a Sponsor physician 
utilizing the same definitions. For a SAE reported by an Investigator as not related that is 
subsequently upgraded to be related by a Sponsor physician, the Investigator will receive a 
notification.
12.5
Unmasking of the Study Treatment
In case of emergency, information on the identity of the masked assigned IP is available to 
Investigators. If the treatment code needs to be broken in the interest of subject safety, the 
Investigator is encouraged to contact an appropriate unmasked Sponsor representative prior 
to unmasking if there is sufficient time. Dependent upon the individual circumstances (ie, 
medical emergency), the code may be broken by contacting the IRT system prior to contact 
with the Sponsor. The Sponsor must be informed in all cases in which the code was broken 
and of the circumstances involved. 
Additionally, the Sponsor may be required to unmask the subject if the AE meets criteria of a 
SUSAR in order to fulfill expedited regulatory reporting requirements.
12.6
Follow-Up of Subjects with Adverse Events
The Investigator is responsible for adequate and safe medical care of subjects during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the trial. Any additional data from these follow-up procedures must be 
documented and available to the Sponsor.
12.7
Pregnancy in the Clinical Trial
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are 
summarized in the protocol’s exclusion criteria.
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Prior to enrollment in the study, female subjects of childbearing potential must be advised of 
the importance of avoiding pregnancy during the trial and the potential risks associated with 
an unintentional pregnancy. During the study, female subjects are to be instructed to contact 
the Investigator immediately if they suspect they might be pregnant. The Sponsor must be 
contacted immediately and a decision will be made regarding continuation of the pregnant 
woman in the study based upon the circumstances surrounding the pregnancy. Pregnancy is 
not reportable as an AE, however, complications may be reportable and will be decided on a 
case by case basis. A Sponsor prepared form will be utilized to capture all pregnancy-related 
information until birth of the child.
13
DATA HANDLING AND ADMINISTRATIVE 
REQUIREMENTS
13.1
Completion of Source Documents and Electronic Case Report 
Forms
The nature and location of all source documents will be identified to ensure that original data 
required to complete the CRFs exist and are accessible for verification by the site monitor. If 
electronic records are maintained, the method of verification must be determined in advance 
of starting the study. At a minimum, source documents should include the following 
information for each subject:
Subject identification (name, sex, race/ethnicity)
Documentation of subject eligibility
Date of informed consent
Dates of visits
Documentation that protocol specific procedures were performed
Results of study parameters, as required by the protocol
Study medication accountability records
Documentation of AEs and other safety parameters (if applicable)
Records regarding medical histories and the use of concomitant therapies prior to and during 
the study
Date of study completion and reason for early discontinuation, if applicable
It is required that the author of an entry in the source documents be identifiable. Direct access 
to source documentation (medical records) must be allowed for the purpose of verifying that 
the data recorded on the CRF are consistent with the original source data. 
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Electronic case report forms will be provided to the sites; only designated individuals may 
complete the CRFs. The CRFs will be submitted at regular intervals based upon the study 
visit schedule. It is expected that all data reported will have corresponding entries in the 
source documents and that the Principal Investigator will review the reported data and certify 
that the CRFs are accurate and complete. No subject identifiers should be recorded on the 
CRFs beyond subject number and demographic information.
13.2
Data Review and Clarifications
The CRF data will be reviewed against the subject’s source data by the study monitors to 
ensure completeness and accuracy. After monitoring has occurred at the clinical sites and the 
CRFs have been submitted, additional data clarifications and/or additions may be needed. 
Data clarifications and/or additions are documented and are part of each subject’s CRFs.
13.3
Regulatory Documentation and Records Retention
The Investigator is required to maintain up-to-date, complete regulatory documentation as 
indicated by the Sponsor, and the Investigator’s files will be reviewed as part of the ongoing 
study monitoring. Financial information is not subject to regulatory inspection and should be 
kept separately. 
Additionally, the Investigator must keep study records and source documents until the 
Sponsor provides written approval for their destruction. If the Investigator retires, relocates, 
or for any other reason withdraws from responsibility of keeping the study records, the 
Sponsor must be notified and suitable arrangements made for retention of study records and 
source documents needed to comply with national and international regulations (generally 2 
years after discontinuing clinical development or after the latest marketing approval).
13.4
Quality Assurance and Quality Control
The Sponsor will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure the study is conducted and data are generated, documented, 
and reported in compliance with the protocol, GCP and applicable regulatory requirements. 
The Sponsor will secure agreement from all involved parties to ensure direct access to all 
study related sites, source data and documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by domestic and foreign regulatory authorities. 
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. Agreements made by the Sponsor with the 
Investigator/Institution and any other parties involved in the study will be provided in writing 
as part of the protocol or as a separate agreement.
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13.5
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established to monitor the safety 
of the trial participants, to ensure that the trial is being conducted with the highest scientific 
and ethical standards, and make appropriate recommendations based on the data seen.
The DMC charter will include the DMC membership and responsibilities, the timing of DMC 
meetings, the content of the analysis report for the DMC meetings, and the communications 
with the Sponsor. The DMC will only make recommendations for changes in study conduct. 
14
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Protocol - Clinical
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Protocol - Clinical
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Simader C, Ritter M, Bolz M, Deak GG, Mayr-Sponer U, Golbaz I. Morphologic Parameters 
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Sommer A, Tielsch JM, Katz, J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, 
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Ophthalmol 2014:132:915-21.
15
APPENDIX
Not Applicable
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