Conditions: Neovascular Age-Related Macular Degeneration Choroidal Neovascularization
Keywords: AMD CNV IVT
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1775
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare brolucizumab (RTH258) ophthalmic solution for intravitreal (IVT) injection at two dosage levels (3 mg and 6 mg) to aflibercept ophthalmic solution for IVT injection (2 mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye.

Detailed description:
Subjects were randomized to brolucizumab 3 mg, brolucizumab 6 mg,and aflibercept 2 mg in a 1:1:1 ratio. Subjects in all treatment arms received 3 monthly loading doses (Day 0, Week 4 and Week 8), followed by a maintenance regimen, until the end of the study (Week 96/Exit). All subjects attended pre-specified visits every 4 weeks.

Subjects in the brolucizumab 3 mg and brolucizumab 6 mg arms followed a q12w/q8w maintenance regimen. Within the q12w/q8w regimen, the initial treatment after the loading phase was q12w (1 injection every 12 weeks). If disease activity was identified by the masked investigator at any of the disease activity assessments, dosing was adjusted to q8w (1 injection every 8 weeks) ("q12w/q8w regimen"). Once subjects were adjusted to the q8w interval, they stayed on that interval until the end of the study.

Subjects in the aflibercept 2 mg arm followed a q8w maintenance regimen until the end of the study.

Results reported up to Week 48 are based on the database locked for the primary analysis at Week 48. Results reported after Week 48 are based on the database locked at the end of study (final analysis).

Arms:
arm 1: Single intravitreal (IVT) injection of brolucizumab ophthalmic solution administered as a 3 mg/50 microliter (μL) dose at Day 0, Week 4, and Week 8, followed by 1 injection every 8 weeks/1 injection every 12 weeks (q8w/q12w) maintenance regimen until study exit arm 2: Single IVT injection of brolucizumab ophthalmic solution administered as a 6 mg/50 μL dose at Day 0, Week 4, and Week 8, followed by q8w/q12w maintenance regimen until study exit arm 3: Single IVT injection of aflibercept ophthalmic solution administered as a 2 mg/50 μL dose at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit

Interventions: intervention 1: Brolucizumab ophthalmic solution intervention 2: Aflibercept ophthalmic solution
Intervention descriptions: intervention 1: Ophthalmic solution for IVT injection intervention 2: Ophthalmic solution for IVT injection

Protocol document:
Prot_002.pdf: 
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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Protocol - Clinical
07-Aug-2017


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
 
 
 
 
 
   
 
  
  
  
  
 
 
 
   
   
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
   
  
 
 
   
  
 
 
 
 
 
  
 
 
  
   
  
 
 
   
  
 
 
 
 
  
 
   
 
 
  
    
 
  
 
   
    
 
 
 
  
 
   
  
  
   
   
    
 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
  
 
   
   
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
   
  
   
      
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
   
 
  
 
 
   
 
 
 
 
  
 
 
  
 
 
 
  
  
 
  
  
   
   
   
  
  
 
  
   
 
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
  
 
 
 
   
 
  
 
  
 
  
 
  
 
 
 
 
 
 
   
 
   
 
  
  
 
  
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
 
 
 
 
 
  
  
 
   
   
 
 
 
 
 
  
   
 
 
 
 
  
 
  
     
 
 
 
  
    
  
 
          
 
 
 
 
 
  
    
   
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
    
   
 
 
 
 
 
 
 
 
  
    
 
  
    
   
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
  
 
  
 
 
 
 
 
   
 
  
  
    
 
 
 
  
 
  
 
 
  
 
 
  
 
  
     
 
  
    
 
 
 
  
 
  
 
  
 
  
   
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
   
    
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 


Page 5 of 84
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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Protocol - Clinical
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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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Protocol - Clinical
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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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Protocol - Clinical
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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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Protocol - Clinical
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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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Protocol - Clinical
07-Aug-2017


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
   
 
 
 
 
  
  
 
  
 
 
 
  
 
    
 
   
   
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
   
 
  
  
   
  
 
 
 
 
 
 
  
   
  
 
  
  
   
   
 
 
  
 
   
  
  
    
 
 
 
 
  
   
  
  
 
 
 
  
 
 
  
        
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
 
  
 
 
  
    
 
      
 
  
 
  
 
 
 
  
 
 
  
 
  
 
 
 
 
    
   
  
  
  
  
 
 
 
   
 
 
 
 
 
 
  
   
    
 
 
 
 
 
  
   
 
  
 
  
 
   
 
  
  
 
  
 
  
  
 
  
  
  
  
   
 
 
  
   
 
 
  
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
  
 
 
 
  
 
  
  
 
 
 
  
   
   
 
 
   
  
 
  
  
 
 
 
 
 
  
 
 
 
  
 
  
 
  
   
 
  
 
 
   
 
  
  
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
  
  
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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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Protocol - Clinical
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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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Page 19 of 84
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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Page 38 of 84
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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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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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
REFERENCES
Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular 
degeneration in Denmark: Year 2000 to 2010. Am J Ophthalmol. 2012;153:209-13.
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP et al. Ranibizumab 
versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 
2009;355:1432-44.
Campbell JP, Bressler SB, Bressler NM. Impact of availability of anti-vascular endothelial 
growth factor therapy on visual impairment and blindness due to neovascular age-related 
macular degeneration. Arch Ophthalmol. 2012;130:794-5.
The CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related 
Macular Degeneration. N Engl J Med. 2011;364:1897-1908.
Chong V, Amoaku W, Alsop J, Osborne A. Effectiveness of quarterly (Q3M) versus monthly 
(QM) ranibizumab according to initial gains in visual acuity - an analysis of 12 month data 
from the EXCITE study. 2013; 54:3816.
Ferris FL. Senile macular degeneration. Review of epidemiologic features. Am J Ophthalmol. 
1983;118:132-51.
Ferris FL, Fine SL, Hyman L. Age-related macular degeneration and blindness due to 
neovascular maculopathy. Arch Ophthalmol. 1984;102:1640-42. 
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD et al. Intravitreal 
aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012; 
119:2537-48.
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Kawasaki R, Yasuda M, Song S, Chen S-J, Jonas J, Wang J. The prevalence of age-related 
macular degeneration in Asians : A systematic review and meta-analysis. Ophthalmology. 
2010;117:921-27.
Kim BJ, Ying GS, Huang J, Levy NE, Maguire MG, CATT Research Group. Sporadic visual 
acuity loss in the comparison of age-related macular degeneration treatments trials (CATT). 
Am J Ophthalmol. 2014;158:128-35.
Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. 
Lancet. 2012;379:1728-38.
Miller JW. Age-Related Macular Degeneration Revisited – Piecing the Puzzle: The LXIX 
Edward Jackson Memorial Lecture. Am J Ophthalmol. 2013;155:1-35.
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N. 
Randomized, double- masked, sham-controlled trial of ranibizumab for neovascular age-
related macular degeneration: PIER Study Year 1. Am J Ophthalmol 2008;145:239-48.
Rein DB, Wittenborn BS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J. Vision Health 
Cost-Effectiveness Study Group. Forecasting age-related macular degeneration through the 
year 2050. Arch Ophthalmol. 2009;127:533-40.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for 
neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-31.
Schmidt-Erfurth U, Guymer Eldem B, Korobelnik JF, Schlingemann RO, Axer-Siegel R, 
Wiedemann P, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in 
neovascular age-related macular degeneration: the EXCITE study. Ophthamology. 2011; 118: 
831-39.
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, et al. 
Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-
six-week results of the VIEW studies. Ophthalmology. 2014; 121:193-201.
Shah AR, Del Priore L V. Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol. 
2007;143:83-89.
Shah AR, Del Priore LV. Natural history of predominantly classic, minimally classic and 
occult subgroups in age-related macular degeneration. Am J Ophthalmol. 2009;116:1901-07.
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Simader C, Ritter M, Bolz M, Deak GG, Mayr-Sponer U, Golbaz I. Morphologic Parameters 
relevant for visual outcomes during anti-angiogenic therapy of neovascular age-related 
macular degeneration. Ophthalmology; 2014;121:1237-45.
Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE. Risk factors for age-related 
macular degeneration: Pooled findings from three continents. Ophthalmology. 2001; 
108:697-704.
Sommer A, Tielsch JM, Katz, J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, 
Witt KA, Ezrine S. Racial differences in the cause-specific prevalence of blindness in East 
Baltimore. N Engl J Med. 1991;14:1412-17.
Spilsbury K, Garrett KL, Shen WY, Constable IJ, Rakoczy PE. Over expression of vascular 
endothelial growth factor (VEGF) in the retinal pigment epithelial leads to the development 
of choroidal neovascularization. Am J Pathol. 2000;157:135-44. 
TAP and VIP Therapy Study Groups. Effect of lesion size, visual acuity and lesion 
composition on visual acuity change with and without verteporfin therapy for choroidal 
neovascularization secondary to age-related macular degeneration: TAP and VIP Report 
No.1. Am J Ophthalmol. 2003;136:407-18.
Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach, K, Probst 
C, Sledge I. The natural history and prognosis of neovascular age-related macular 
degeneration: a systemic review of the literature and meta-analysis. Ophthalmology. 
2008;115:116-26.
Ying GS, Kim BJ, Maguire MG, Huang J, Daniel E, Jaffe GJ, et al. Sustained visual acuity 
loss in the comparison of age-related macular degeneration treatments trials. JAMA 
Ophthalmol 2014:132:915-21.
15
APPENDIX
Not Applicable
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SAP_001.pdf: 
Alcon - Business Use Only Statistical 
Effective Date: 12-Jun-2017 
Analysis Plan 
Document: TDOC-0053528 
Status: Effective 
Version: 2.0; Most-Recent; Effective; CURRENT 
Printed By: 
Print Date: 
 
 
 
 
 
 
 
 
Clinical Development 
 
 
RTH258/Brolucizumab 
 
RTH258A2301 (HAWK) / NCT02307682 
 
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 
 
Statistical Analysis Plan (SAP) 
 
 
Author: 
 
Document type: 
SAP Core body 
Document status: 
Final 2.0 
Release date: 
12-June-2017 
Number of pages: 
55 
 
 
 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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CURRENT 
Page2 
RTH258A2301 
Document: TDOC- 0053 528 
Version: 2.  o;  Mos   t - Rec en t ; 
For busine s s   us e  o n ly 
Ef f e c ti ve ; 
Statn:.sEf f e c t  i ve 
"Novan1 
SAP V2.0 
 
 
 
 
Document History - Changes compared to previous final version 
 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and title 
impacted (Current) 
24-Feb-2017 
Prior to 
DB lock 
Creation of final version 
NIA 
First version 
(Vl.O) 
approved in 
documentum 
system. 
NIA 
12-June-2017 
Prior to 
DB lock 
Creation of amendment-I 
• 
futroduction of 
additional hypotheses 
testing in relation to 
secondaiy endpoints 
• 
Adjustments in relations 
to observed protocol 
deviations and analysis 
restrictions, e.g. detailed 
specifications for the 
per-protocol set 
including censoring and 
the assessment of the 
q12 proportion based on 
a time-to-event analysis 
• 
• 
Addition of "AEs of 
potential relevance to 
intravitrealanti-VEGF 
class" under "Adverse 
events (AEs)" sub- 
section (2.8.2) 
Updated. 
Sub-sections 1.2, 2.2, 2.4, 
2.5. 2.6, 2.7, 2.8 and 5 


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Effective Date: 12-Jun-2017 
Analysis Plan 
Document: TDOC-0053528 
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Status: Effective 
Novartis 
SAP V2.0 
For business use only 
Page 3 
RTH258A2301 
 
 
 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................. 6 
1.1.1 
Randomization ........................................................................................ 7 
1.1.2 
Masking ................................................................................................... 7 
1.1.3 
Primary analysis ...................................................................................... 8 
1.1.4 
Data monitoring committee (DMC) ........................................................ 8 
1.2 
Study objectives and endpoints................................................................................ 8 
1.2.1 
Objectives ................................................................................................ 8 
1.2.2 
Endpoints................................................................................................. 9 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
All-Enrolled and All-Randomized Analysis Sets .................................. 13 
2.2.2 
Efficacy Analysis Sets ........................................................................... 13 
2.2.3 
Subgroups of interest ............................................................................. 14 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 14 
2.3.1 
Subject disposition ................................................................................ 15 
2.3.2 
Demographic and baseline characteristics ............................................ 15 
2.4 
Treatments (study treatment / compliance, rescue medication, concomitant 
therapies) ................................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Medical history, prior/concomitant medication and concomitant 
procedures ............................................................................................. 16 
2.5 
Analysis of the primary and first key secondary objectives .................................. 17 
2.5.1 
Primary and first key secondary endpoints ........................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 18 
2.5.4 
Supportive analyses ............................................................................... 18 
2.6 
Analysis of the second and third key secondary objectives ................................... 19 
2.6.1 
Second and third key secondary endpoints ........................................... 19 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.6.4 
Supportive analyses ............................................................................... 21 
2.7 
Analysis of additional secondary efficacy objective(s) ......................................... 24 


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2.7.1 
Secondary endpoints ............................................................................. 24 
26 
2.7.3 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.7.4 
Handling of missing values/censoring/discontinuations ....................... 30 
2.8 
Safety analyses ....................................................................................................... 30 
2.8.1 
Extent of exposure ................................................................................. 31 
2.8.2 
Adverse events (AEs) ............................................................................ 31 
2.8.3 
Deaths .................................................................................................... 36 
2.8.4 
Laboratory data ..................................................................................... 36 
2.8.5 
Other safety data.................................................................................... 39 
2.8.6 
Presence of geographic atrophy ............................................................ 41 
2.8.7 
Post-injection assessment ...................................................................... 41 
2.8.8 
Presence of anti-drug antibody (ADA) ................................................. 41 
2.9 
Pharmacokinetic endpoints .................................................................................... 42 
2.10 
Subject-reported outcome ...................................................................................... 42 
2.10.1 
Visual function questionnaire (VFQ-25)............................................... 42 
2.11 
Interim analysis ...................................................................................................... 43 
3 
Sample size calculation ..................................................................................................... 43 
4 
Change to protocol specified analyses ............................................................................... 44 
5 
Appendix ........................................................................................................................... 45 
5.1 
Imputation rules ..................................................................................................... 45 
5.1.1 
AE date imputation ............................................................................... 45 
5.1.2 
Concomitant medication date imputation ............................................. 46 
5.2 
Statistical models ................................................................................................... 48 
5.2.1 
Primary and first key secondary analysis .............................................. 48 
5.2.2 
Key secondary analysis ......................................................................... 50 
5.3 
Subject evaluability and censoring ........................................................................ 51 


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List of abbreviations 
 
AE 
Adverse event 
AR 
Analysis Restrictions 
nAMD 
Neovascular Age-related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity 
CI 
Confidence Interval 
CNV 
Choroidal Neovascularization 
CSFT 
Central Subfield Thickness 
CSFTns 
Central Subfield Thickness-neurosensory retina 
CSFTtot 
Central Subfield Thickness-total 
CSM 
Clinical Site Management 
CSR 
Clinical Study report 
CTM 
Clinical Trial Management 
DA 
Disease Activity 
DEP 
Deviations and Evaluability Plan 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IVR 
Interactive Voice Response 
IVT 
Intravitreal 
LSM 
Least Squares Mean 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NMQ/CMQ 
Novartis MedDRA Query/Custom Novartis MedDRA Query 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
q8 
Treatment every 8 weeks 
q12 
Treatment every 12 weeks 
QoL 
Quality of Life 
RAP 
Retinal Angiomatous Proliferation 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set 
SE 
Standard Error 
SOC 
System Organ Class 
SoC 
Standard of Care 
TFLs 
Tables, Figures, Listings 
VA 
Visual Acuity 
WHO 
World Health Organization 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods 
that will be used for the Clinical Study Report (CSR) of study RTH258A2301. 
Data will be analyzed according to the data analysis Section 11 of the study protocol which 
will be available in Appendix 16.1.1 of the CSR. Important information is given in the 
following sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR. 
The SAP will be finalized before treatment unmasking. Any changes to the SAP after 
approval will be documented. 
 
1.1 
Study design 
This is a prospective, randomized, double masked, multicenter, three arm study comparing the 
efficacy and safety of RTH258 intravitreal (IVT) injections versus aflibercept IVT injections 
in subjects with neovascular age-related macular degeneration (AMD). 
The three treatment arms are: 
 
Arm 1: Brolucizumab 3 mg/50 μL (a.k.a RTH258 3 mg/50 μL) 
Arm 2: Brolucizumab 6 mg/50 μL (a.k.a RTH258 6 mg/50 μL) 
Arm 3: Aflibercept 2 mg/50 μL (a.k.a Eylea 2 mg/50 μL) 
 
Subjects in all the three arms will have visits every 4 weeks through Week 96. 
According to protocol, approximately 330 subjects per arm (total 990 subjects) will be 
randomized in this trial. More details of the sample size calculation can be found in Section 3. 
By the time this first amendment is implemented, 1,082 subjects were randomized in the study. 
Subjects in the RTH258 3 mg (Arm 1) and RTH258 6 mg (Arm 2) will be initially injected 3 
times at 4 week intervals, at Visit 1/Baseline, Visit 2/Week 4 and Visit 3/Week 8. 
Following these 3 loading doses, each subject will be injected every 12 weeks (q12) up to 
Visit 25/Week 92 unless there is disease activity assessed 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, Visit 22/Week 80 or Visit 25/Week 92. If disease activity is identified, the 
subject will be reassigned to receive injections every 8 weeks (q8) thereafter, up to Week 
88/92. Refer to protocol Section 10.1 for disease activity criteria. 
In Arm 3, aflibercept 2 mg, (EYLEA®, comparator) will be injected 3 times at 4 week 
intervals (Visit 1/Baseline, Visit 2/Week 4 and Visit 3/Week 8), followed by injections every 
8 weeks (q8) up to Visit 24/Week 88. 
The dosing schedule by treatment is presented graphically below. 


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Figure 1 Dosing schedule by treatment 
 
 
1.1.1 
Randomization 
A member of the Statistical Programming group at Alcon who is not part of the study team 
will generate the randomized allocation for the study treatment assignment based on a 
randomization plan providing study specific criteria for randomization including block size 
and randomization ratio. Treatment is assigned to subjects through the Interactive Response 
Technology (IRT) system. Each subject number is associated with a treatment group 
according to the randomized allocation generated using the computer software SAS version 
9.2 PROC PLAN. Subjects are assigned subject identification numbers sequentially according 
to time of randomization. 
Eligible subjects will be randomized at visit 1/Baseline 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 absence of polypoidal choroidal vasculopathy (PCV). PCV is 
identified at the screening visit using indocyanine green (ICG) imaging and confirmed by the 
Central Reading Center (CRC). The randomization schedule will be blocked to ensure a 
balance of treatment allocations across the study. 
 
1.1.2 
Masking 
This is a double–masked study. The investigator, investigator staff (except for the unmasked 
site personnel and unmasked injecting physician), subjects and Sponsor personnel (except for 
those who have been delegated responsibility for working with the IP) involved with conduct 
of the trial are masked with regard to treatment assignment while the study is in progress. 
Sponsor personnel who have access to treatment codes (e.g., randomization specialist, 
personnel directly involved with bioanalysis of serum samples, unmasked monitors 
performing investigational product accountability and Clinical Supplies personnel) will not 
divulge the codes to subjects, Investigators, site staff, and Sponsor personnel involved in the 
conduct of the study. Masking is maintained by providing sham injections. With this setup, 
subjects will continue to receive masked treatment (active or sham) monthly through the 
planned study duration (96 Weeks) to allow for further masked evaluation of efficacy and 
safety. Treatment masking will remain intact also for Investigators, and staff from the Sponsor 


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who have contact with subjects or Investigators or those who are involved in the direct 
conduct of the study until the final database lock (Week 96) has occurred. 
The primary analysis at Week 48 will be performed with an unmasking of specified 
individuals from the Sponsor who are not involved in the direct conduct of the trial. The 
biostatistician who is directly involved in the conduct of the study will remain masked to 
treatment assignments while the study is in progress. 
The document ‘Process map for maintaining the mask during protocol deviation and analysis 
restriction determination for RTH258 in wet AMD’ summarizes the procedures and actions to 
maintain masking to the actual treatment assignment during the pre- DBL subject evaluability 
assessment for the Phase III studies CRTH258A2301 and CRTH258A2302. This document 
was finalized prior to unmasking of these studies and is located in R&D Document 
Compliance Manager (RDDCM) system, Document ID: TDOC- 0053869. 
Details on the conduct and logistics of the unmasked team that will perform the primary 
analysis are provided in the document ‘Maintaining the masking of the Phase III studies 
(CRTH258A2301 and CRTH258A2302)’ finalized prior to unmasking of these studies and 
located in “/CREDI Projects/R/RTH258A/CREDI Studies/RTH258A2301/Administrative 
Files (study level)/Validation and Planning documents - CRTH258A2302_Maintaining the 
Mask-20170518”. This document summarizes procedures and actions implemented by 
Novartis to preserve the blinding of these Phase III studies after the Week 48 interim DBL 
and the corresponding unmasking. 
 
1.1.3 
Primary analysis 
The primary safety and efficacy analysis will be based on the Week 48 data, i.e. all data up to 
and including Week 48. This analysis will be performed once all subjects completed their 
Week 48 visits or terminated the study before Week 48, while subjects continue to receive 
masked treatment through the planned study duration of 96 Weeks. The analysis of the data 
collected after the Week 48 visit will be performed once all subjects completed or 
discontinued from the study. 
 
1.1.4 
Data monitoring committee (DMC) 
An independent Data Monitoring Committee (DMC) will be established to monitor the safety of 
the trial participants, and make appropriate recommendations based on the safety data reviewed. 
Details on the DMC membership, responsibilities, timing of meetings, data to be reviewed, 
and communication with the Sponsor will be described in the DMC charter. All statistical 
analysis conducted for the purpose of the DMC is outside the scope of this SAP and is 
covered in the DMC charter and other supporting documents. The unmasked analyses for the 
DMC will be conducted by an independent contract research organization. Access to the 
unmasked analysis results will be limited to the DMC members only. 
 
1.2 
Study objectives and endpoints 
1.2.1 Objectives 
Primary objectives: 


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• 
To demonstrate that RTH258 is not inferior to aflibercept with respect to the change in 
best-con ected visual acuity (BCVA) from Baseline to Week 48 
Key secondary objectives: 
• 
To demonstrate that RTH258 is not inferior to aflibercept with respect to the change in 
BCVA from Baseline averaged over the period Week 36 to Week 48 
• 
To estimate the proportion of ql2 (1 injection every 12 weeks) subjects up to Week 48 in 
the RTH258 treatment arms 
• 
To estimate the predictive value of the first ql2 cycle for maintenance of ql2 treatment up 
to Week 48 in the RTH258 treatment arms 
Other secondary objectives: 
• 
To evaluate the efficacy of RTH258 relative to aflibercept over the time period up to 
Week 96 by assessing changes in: 
o BCVA 
o Anatomical parameters of disease activity including central subfield thickness 
(CSFT), choroidal neovascularization (CNV) area, presence of subretinal, 
intraretinal, and subRPE fluid, and absence of intraretinal and subretinal fluids 
o Presence of ' q8 treatment need' includingassessmentof ql2 status for subjects 
in the RTH258 3 mg and 6 mg treatment arms 
o Visual function-related patient-reported outcomes following treatment with 
RTH258 relative to aflibercept 
• 
To assess the safety and tolerability of RTH258 relative to aflibercept 
 
1.2_2 
Endpoints 
 
1.2.2.1 
Efficacy Endpoinst 
Primary Endpoint 
The primary efficacy endpoint is change in BCVA from Baseline to Week 48 
Key Secondary Endpoints 
The key seconda1y efficacy endpoints are: 
• 
Average change in BCVA from Baseline over the period Week 36 through 48. For 
each subject, this endpoint is defined as the average of the changes from Baseline to 
Weeks 36, 40, 44, and 48. 
• 
ql2 treatment status at Week 48 (for subjects randomized to RTH258 3 mg and 6 mg 
only) 
• 
ql2 treatment status at Week 48 within the subjects with no q8 need during the first 
ql2 cycle (Week 16, Week 20) (for subjects randomized to RTH258 3 mg and 6 mg 
only). 
Additional Secondary Efficacy Endpoints 


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• 
Change in BCVA from Baseline to each postbaseline visit 
• 
Average change in BCVA from Baseline over the period Week 84 through Week 96 
• 
Average change in BCVA from Baseline over the period Week 4 to Week 48/96 
• 
Average change in BCVA from Baseline over the period Week 12 to Week 48/96 
• 
Gain in BCVA of 15/10/5 letters or more from Baseline to each postbaseline visit 
• 
Number and percentage of subjects with BCVA of 73 letters or more at each visit 
• 
Loss in BCVA of 15/10/5 letters or more from Baseline to each postbaseline visit 
• 
ql2 treatment status at Week 96 (for subjects randomized to RTH258 3 mg and 6 mg 
only) 
• 
ql2 treatment status at Week 96 within the subjectswith no q8 need during the first 
ql2 cycle (Week 16, Week 20) (for subjects randomized to RTH258 3 mg and 6 mg 
only) 
• 
q8 treatment need at Week 16 
• 
Change in CSFTtot from Baseline to each postbaseline visit 
• 
Average change in CSFTtot from Baseline over the period Week 36 through Week 48/ 
over the period Week 84 through Week 96 
• 
Average change in CSFTtot from Baseline over the period Week 4 to Week 48/96 
• 
Change in CSFTns from Baseline to each postbaseline visit 
• 
Average change in CSFTns from Baseline over the period Week 36 through Week 48/ 
Week 84 through Week 96 
• 
Average change in CSFTns from Baseline over the period Week 12 through Week 
48/96 
• 
Change in area of CNV within the lesion from Baseline to Weeks 12, 48 and 96 
• 
Presence of subretinal fluid (central subfield) at each postbaseline visit 
• 
Presence of intraretinal fluid (central subfield) at each postbaseline visit 
• 
Presence of sub RPE fluid (central subfield) at each postbaseline visit 
• 
Simultaneous absence of subretinal and intraretinal fluid (central subfield) at each 
postbaseline visit 
• 
Number of visits with simultaneous absence of subretinal and intraretinal fluid (central 
subfield) during Week 36 to Week 48 
• 
Presence of subretinal hemoIThage  (centra l s u b fi eld)  at each assessment visit 
• 
Presence of intraretinal hemoIThage  (centra l s u b fi e ld) at each assessment visit 
• 
Simultaneous absence of subretinal and intraretinal hemoIThage (ce n tral subfield) at 
each assessment visit 


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• 
Change in patient- rep01ied outcomes (VFQ-25) total and subscale scores from 
Baseline to Weeks 24, 48, 72 and 96 
1.2.2.2 
Safety Endpoints 
The safety endpoints are based on the following assessments: 
• 
Extent of exposure 
• 
Adverse events 
• 
General physical exam 
• 
Vital signs 
• 
Laborato1y tests (Blood chemistry , hematology and urinalysis) 
• 
Loss in BCVA 
• 
Slit-lamp examination (aqueous reaction [cells and flare]) 
• 
Fundus exam (retinal hemon hage/detachment, vitreal hemonhage density and viu-eo us 
ce lls) 
• 
Co lor fund us photography (presence of geographic au-ophy) 
• 
Fundus autofluorescence (for presence and area of atrophy) 
• 
IOP 
• 
Post-injection assessment (gross assessment of vision, IOP, status of  cenu·al  retinal 
arte1y and presence of retinal detachment/new inu-aoc ul ar he m o n hage) 


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• 
Anti-diug antibodies (ADA) and Serum concentration ofRTH258 
 
2 
Statistical methods 
2.1 
Data analysis general information 
 
The prima1y analysis at Week 48 and the final analysis after all subjects completed / 
te1minated the study will be performed by the Biostatistics and statistical programming groups 
of Nova1tis using SAS 9.4 or above. 
Tables will be presented based on the unit subject, with ocular parameters presented 
separately for the study- and fellow-eye as applicable. 
Continuous variables will be summarized using the number of observations, mean, median, 
standard deviation, standard en ors, quartiles, minimum and maximum values. Categorical 
variables will be summarized with the number of observations, the number of  observations  for 
each categ01y and the co1Tes ponding frequenc  y  and percent. Where appropriate, two-sided  
95% confidence inte1v als for point estimates of the mean or prop01tion will be provided. Point 
estimates and two-sided 95% confidence inte1vals of treatment group  differences  and p-values 
will be provided as appropriate. 
Outputs will be presented by treatment and in addition with the overall column for the study 
population descriptions at baseline. Listings will include the following identifying variables: 
treatment, investigator number, country , subject number, age, sex, race, and visit. In addition, 
ocular assessments will include identification of the study and fellow eye. 
 
2_.1 1 General definitions 
lnvestigational product (IP) or ti·eatment refers to both Broclucizumab 3mg, 6mg and 
Aflibercept 2mg IVT injections. 
Baseline (Day 1) is the date of the first study treatment in the study. The Baseline value for 
efficacy and safety variables is the last available value collected prior to the first treatment 
which can occur at the Baseline or Screening visits. 
All data collected after the first study treatment are defined as post-Baseline. The 
study day for a post-Baseline scheduled or unscheduled visit is defined as: 
Study day = (date of visit) - (date of first study ti·eatment) + 1 
The study day for a scheduled or unscheduled visit before Baseline is defined as 
Study day = (date of visit) - (date of first study ti·eatment) 
End of study/end of treat ment day mapp ing: 
The end of study date (from the ' Visit date' fo11n in CRF) is the date when a subject 
completes  or  discontinues the  study.  The   " Date   of  Last  Exposure"  (from  CRF 
' Exposme' form) is the date of the last study treatment on or prior to the end of study 
date. For rep01ting data by visit in outputs, the end of study/end of treatment visit will 
be allocated to the actual (rep01ted) visit number. If end of study date is not on a 


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scheduled visit, then end of study visit will be allocated based on study day to the 
closest future scheduled study visit. 
Unscheduled visits: 
All data collected at unscheduled visits will not be used in ‘by-visit’ tabulation or 
graphs, but they will be included for analyses based on all post-Baseline values such 
as LOCF imputation, safety narratives, summary of maximum decrease or increase 
from baseline for laboratory and vital signs data. 
All data collected at unscheduled visits will be included in listings. 
 
2.2 
Analysis sets 
Subject evaluability based on pre-specified deviations from the protocol and/or analysis 
requirements and their impact on analysis sets will be determined prior to locking the database 
for the primary analysis at Week 48 and breaking the masked treatment assignment code. 
Before the Week 48 database lock, the relevant protocol deviations and analysis restrictions will 
be specified in the deviations and evaluability plan (DEP) document with the analysis restrictions 
also presented in Section 5.3. The corresponding identifications at the subject level including 
censoring will be captured in the database and locked prior to unmasking. 
 
2.2.1 
All-Enrolled and All-Randomized Analysis Sets 
All-enrolled analysis set includes all subjects who signed informed consent and are assigned 
subject numbers. 
All-randomized analysis set (RAN) includes all subjects who were randomized in IRT. 
 
2.2.2 
Efficacy Analysis Sets 
All efficacy analyses will be conducted according to the randomized treatment assignment. 
 
2.2.2.1 
Full analysis set 
The full analysis set (FAS) includes all randomized subjects who receive at least one IVT 
injection of the study treatment. The full analysis set will serve as the primary analysis set for 
all efficacy analyses. The FAS represents the analysis set which is as close as possible to the 
intent-to-treat (ITT) principle of including all randomized subjects. 
 
2.2.2.2 
Per protocol analysis set 
Supportive analyses of the primary and secondary endpoints will include analysis using the 
per protocol set (PPS). PPS is a subset of the FAS and will exclude subjects with protocol 
deviations and analysis restrictions that are expected to majorly affect the validity of the 
assessment of efficacy at Week 48 including for e.g. lack of compliance (including missed 
treatments and treatment misallocation), missing data, prohibited concomitant medication and 
deviation from inclusion/exclusion criteria. Discontinuation from treatment due to lack of 
efficacy and/or safety does not constitute a reason for exclusion from the PPS. 
Before the Week 48 database lock the relevant protocol deviations and analysis restrictions as 
specified in the DEP will be identified at the subject level in the database. Censoring applied 
in relation to the specific PDs / ARs is described in Section 5.3 and the DEP. 


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When assessing the robustness of the overall efficacy conclusions, equal impmi ance will be 
given to the FAS and PPS results understanding that a robust study will demonstrate similar 
conclusions from both analysis sets. Inconsistencies in key efficacy study results between the 
FAS and PPS will be examined and discussed in the clinical study report (CSR). 
 
2.2.2.3 
Safety Analysis Set 
The safety analysis set (SAF) will include all subjectswho receive at least one IVT injection. 
Subjects in the safety analysis set will be analyzed according to the treatment arm from which 
they received majority of treatments up to and including Week 44. 
To capture potential procedure related AEs occuning in subjects without having received at 
least one IVT injection, all AEs of randomized subjects not belonging to the SAF occuning at 
or after the day of randomization will be listed separately. 
 
2.2.3 
Subgroups of interest 
The subgroups of interest are listed below: 
• 
Age catego1y (<75 years and ?.75 years) 
• 
Gender (male and female) 
• 
Baseline BCVAcategories (:S55, 56 -70, ?.71 letters) 
• 
Baseline CS FTcatego1y (<400,  ?.400 microns) 
• 
Baseline lesion type ( predominantly classic, minimally classic, occult) 
• 
Baseline CNV lesion size (tertiles) 
• Baseline lesion size by lesion type (predominant classic vs. minimally classic/occult) 
(tertiles) 
• 
Baseline fluid status (intraretinal fluid (IRF), subretinal fluid (SRF),   sub-retinal 
pigment epithelium (sub-RPE) fluid) 
• 
Japanese ethnicity: Japanese vs non-Japanese 
• 
Baseline polyps status (present/absent) from ICGA at Screening (Japanese sites only) 
Subgroup analysis will be performed for the primaiy and key secondaiy efficacy variables. 
More details can be found in Sections 2.5.4, and 2.6.4. 
 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
Subject characteristics and study conduct summaries include tables and listings such as a 
subject disposition table, demographics and baseline characteristics tables, listing of treatment 
assignment by investigator, summa1y of screen failures by reason and listing of subjects 
excluded from the full analysis, per-protocol and safety analysis  sets including the 
conesponding reasons and censoring. 
No tests for differences in background and demographic characteristics between treatment 
groups will be perfmmed. Potential related differences will be assessed based on clinical 
relevance. 


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2.3.1 
Subject disposition 
Subject disposition table will be based on the All-randomized analysis set. The following 
summaries will be included in the disposition table: number and percent of subjects who were 
randomized and treated (= received at least one injection), completed the study, discontinued 
from treatment / study overall and by reason of discontinuation. Percentages will be based on 
the number of subjects who are randomized. If there were dosing errors where subjects 
received treatment other than what they were randomized to, separate summaries will be 
presented based on ‘as treated’, while the ‘as treated’ status will be derived from the majority 
of treatments received. 
A subject is considered to have completed a study period (Week 48 / Week 96) if he/she did 
not discontinue study prior to the end of this period. Discontinuation at Week 48 with exit 
visit assessment performed is considered as ‘completed’ for the Week 48 analysis. 
Number and percent of subjects who failed screening (i.e. were not randomized) will be 
presented by reason using the All-enrolled analysis set. Appropriate table and listing of all 
screen failures along with the corresponding reason will also be presented as necessary. 
Number and percent of subjects who were excluded (i.e. not evaluable) from each of the SAF, 
FAS, and PPS will be presented using the All-randomized analysis set. A listing of subjects 
along with the analysis set that they were excluded from and the corresponding reasons will 
also be presented. 
Number and percent of subjects with major protocol deviations and analysis restrictions will 
be presented by deviation/restriction category. A listing of all relevant deviations will be 
presented. 
A listing of subjects who discontinue from the study and/or treatment early will be provided. 
The listing will identify the visits completed and when the study or treatment was 
discontinued including the corresponding reasons. 
 
2.3.2 
Demographic and baseline characteristics 
Demographic table will include: age (both as a continuous variable and using categories (≤64, 
65 to 74, 75 to 84, and ≥85), gender, race, ethnicity. Demographic summary tables will be 
presented for the all-randomized, SAF, FAS and PPS. 
Baseline characteristics table will include: primary diagnosis of nAMD, time since diagnosis 
of neovascular AMD (days), whether neovascular AMD is unilateral or bilateral, BCVA (both 
as a continuous variable (letters read) and using categories (≤55, 56-70, ≥71 letters read), type 
of CNV (predominantly classic, minimally classic, occult only), CNV location (subfoveal, 
juxtafoveal, extrafoveal, absent), area of CNV associated with the lesion (mm2), presence of 
subretinal fluid, presence of intraretinal fluid, presence of sub RPE fluid, presence of polyps 
(Japan sites only), presence of retinal angiomatous proliferation (RAP), central subfield 
neurosensory retinal thickness (CSFTns) and central subfield thickness total (CSFTtot) (both 
as a continuous variable and using categories (<250, ≥250 µm) / (<400, ≥400 µm) 
respectively). The baseline characteristics table will be presented separately for the study and 
fellow eye. 
A subject listing containing all demographics information by investigator will be presented 
using the All-randomized analysis set. The listing will also include columns for the 


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randomized treatment, the number of active injections by treatment and the majority of the 
actual treatment received for a subject. 
 
2.4 
 Treatments (study treatment/ compliance, rescue 
medication, concomitant therapies) 
2.4.1 
Study treatment/ compliance 
Extent of exposure to investigational product is calculated as the number of injections 
received. The following summaries will be presented based on the FAS and PPS. 
• 
Overall number of treatments will be presented separately (active and sham, active only, 
sham only) in the following time periods: 
o Baseline to Week 8 
o Week 12 to Week 44 
o Baseline to Week 44 
o Week 48 to Week 92 
o Baseline to Week 92 
• 
Treatment exposure by visit: The number and percent of subjects who received active, 
sham injections, missed a treatment (active or sham) and missed visits will be presented 
separately by visit and by treatment status (q8, ql 2) for the Brolucizumab treatment 
groups. 
• 
Frequencyof all observed dosing patterns up to and including Week 44 and up to Week 
92 differentiating between active and sham treatments, missed treatments and wrong 
treatments will be presented. 
• 
ql 2/q8 allocation for RTH258 subjects by visit: Number and percent of RTH258 subjects 
on ql 2 and q8 including the number of subjects switched from ql2 to q8 with related 
reasons. 
 
2.4.2 
Medical history, prior/concomitant medication and concomitant 
procedures 
 
2.4.2.1 
Medical history 
Medical history (ocular and non-ocular) will be tabulated by systemorgan class and prefeITed 
te1m of the MedDRA dictionary using the all-randomized analysis set. Ocular events will be 
presented separately by study and fellow eye. A listing of all medical histmy data will be 
provided. 
 
2.4.2.2 
Prior medication 
Prior medications (ocular and non-ocular) will be summarized using number and percentage 
of subjects by ATC class and prefeITed te1m according to the WHO Drug reference list 
dictiona1y using the all-randomized analysis set. Prior medications are those that have a start 
date p1i or to the first IVT injection date. Ocular medications will be presented separately for 
the study and fellow eye. Prior medications will be classified in addition as whether or not 


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they were ended prior to the first IVT injection date. A listing of all prior medications will be 
provided. 
 
2.4.2.3 
Concomitant medication 
The number and percentage of subjects taking concomitant medications will be summarized 
by ATC class and prefen-ed term according to the WHO Drng Reference List dictionary using 
the safety analysis set. Medications that were taken during the trnatment period, including 
those that struted prior to first injection but continued after t1eatment sta1t, will be summarized 
as concomitant medications. Concomitant medications will be classified in addition as 
whether or not they sta1ted prior to first IVT injection for ocular medications, sepru·ate 
summaries will be presented for study and fellow eye. A listing of all concomitant medication 
will be provided. 
 
2.4.2.4 
Concomitant procedures 
The number and percentage of subjects who had procedures done during the study will be 
summarized by system organ class and prefe1Ted tenn according to the MedDRA dictionruy 
using the safety analysis set. For oculru·p rocedures, separate summaries will be presented for 
study and fellow eye. A listing of all concomitant procedures will be provided. 
 
2.5 
Analysis of the primary and first key secondary 
objectives 
2.5.1 
Primary and first key secondary endpoints 
• 
The primary efficacy endpoint is change in BCVA from baseline to Week 48. Best- 
co1Tected v isual acuity will be measured based on the procedures developed for the 
Early Treatment Diabetic Retinopathy Study (ETDRS) and the results will be repo1ted 
in letters. 
• 
The first key seconda1y endpoint is average change in BCVA from Baseline over the 
period Week 36 through Week 48. For each subject, this endpoint is defined as the 
average of the changes from baseline to Weeks 36, 40, 44 and 48. The motivation for 
the choice of this endpoint is that, averaging the BCVA values over Week 36 to Week 
48 will smooth out both random fluctuations and potential trough and peak values 
during the different treatment cycles. During the period Week 36 to Week 48, 
aflibercept and RTH258 subjects on q8 will have 2 assessments 4 weeks after the last 
dose, and 2 assessments 8 weeks after the last dose. RTH258 subjects on a q12 
regimen will have 2 assessments 4 weeks after the last dose, 1 assessment 8 weeks 
after the last dose, and 1 assessment 12 weeks after the last dose. 
The prima1y and first key seconda1y efficacy analyses will be based on the FAS with last-
obse1vation-c1aTied-f  01ward (LOCF) imputation of missing BCVA values. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypotheses for the prima1y and first key secondary endpoints are to 
demonstrate noninferiority of RTH258 6 mg and 3 mg to aflibercept 2 mg within a margin of 
4 letters. 


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The following 4 hypotheses will be tested in the pre-specified hierarchical sequence according 
to their numbering (HAn, n=1, 2, 3, 4). 
 
48 = Week 48, 36-48 = Week 36 through 48, R6(3)=RTH258 6(3) mg, A=Aflibercept 2 mg 
 
 
H01: μ48R6 - μ48A ≤ -4 letters vs 
HA1: μ48R6 - μ48A > -4 letters 
H02: μ36-48R6 - μ36-48A ≤ -4 letters vs 
HA2: μ36-48R6 - μ36-48A > -4 letters 
H03: μ48R3 - μ48A ≤ -4 letters vs 
HA3: μ48R3 - μ48A > -4 letters 
H04: μ36-48R3 - μ36-48A ≤ -4 letters vs 
HA4: μ36-48R3 - μ36-48A > -4 letters 
 
μ48R6, μ48R3 and μ48A being the corresponding unknown true mean BCVA changes from 
Baseline to Week 48 and μ36-48R6, μ36-48R3 and μ36-48A being the corresponding unknown true 
mean values for the average change in BCVA from Baseline over the period Week 36 through 
48. 
The primary and first key secondary endpoints will be analyzed by fitting pair-wise analyses 
of variance (ANOVA) models with treatment, baseline BCVA categories (≤55, 56-70, ≥71 
letters) and age categories (<75, ≥75 years) as fixed effects. Least square means for each 
treatment group and treatment differences together with corresponding two-sided 95% CIs 
will be derived from the fitted model. Non-inferiority is demonstrated if the lower limit of the 
two-sided 95% confidence interval for the corresponding treatment difference (RTH258 – 
aflibercept) is greater than -4 letters. 
The 4 hypotheses listed above will be tested in the pre-specified hierarchical sequence 
according to their numbering (HAn, n=1, 2, 3, 4). Consequently, confirmatory testing of the 
second, third and fourth hypotheses requires rejection of each preceding null hypothesis. In 
this setting, each hypothesis will be assessed at a one-sided significance level of 0.025, while 
keeping the global type I error rate at 0.025. 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data will be imputed using last observation carried forward (LOCF) method. 
Observed values from both scheduled and unscheduled visits will be used for the LOCF 
imputation. For subjects with no postbaseline value, the baseline value will be carried forward. 
For subjects who discontinue treatment but continue in the study, the efficacy data will be 
censored at the time the subject started alternative anti-VEGF treatment in the study eye. No 
other censoring is applied within the FAS analysis of the primary and first key secondary 
endpoints. Censored or missing data will be imputed by the last observation prior to receiving 
alternative anti-VEGF treatment. 
 
2.5.4 
Supportive analyses 
The following supportive analyses will be done: 
1. Descriptive statistics for the primary and first key secondary endpoints will be 
presented based on LOCF imputation for missing /censored values using the FAS and 


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PPS. In addition observed data with and without censoring will be presented 
descriptively using the FAS. For the PPS, observed values will be presented 
descriptively excluding censored data. As a result within these ‘observed data’ – 
analyses for the primary endpoint, all subjects with missing Week 48 BCVA value  
will not be considered. Similarly, for the endpoint ‘average change in BCVA from 
Baseline over the period Week 36 through Week 48’, only non-missing values at 
Weeks 36, 40, 44, and 48 will be averaged for the ‘observed data’ analysis. 
2. ANOVA using the PPS with LOCF imputation for missing/censored values. The same 
model as in the primary analyses will be fitted for this supportive analysis. 
3. Mixed model repeated measures (MMRM) using the FAS and PPS with observed data 
(including censoring). The MMRM will include treatment, visit, baseline BCVA 
category, age category and treatment by visit interactions as fixed-effect terms and 
visit as a repeated measure. An unstructured covariance matrix will be used to model 
the within-subject error. For the MMRM analysis: 
a. The treatment difference at Week 48 will be estimated using the LSM and 95% 
percent confidence interval. 
b. For the endpoint of average change from Baseline over the period Week 36 
through Week 48, a SAS code utilizing the ESTIMATE statement in PROC 
MIXED will be provided in the programming specification document to obtain 
the LSM estimate for the corresponding treatment difference and 95% 
confidence interval. 
c. If an MMRM model with unstructured covariance matrix does not converge, a 
more restricted covariance matrix can be considered in the following order 
until convergence is reached: variance components (VC), compound symmetry 
(CS), first-order autoregressive (AR) and Toeplitz (TOEP). 
4. Subgroup analyses will be conducted to assess the consistency of treatment effect 
across various subgroups described in Section 2.2.3. The FAS with missing values 
imputed using LOCF and observed case analysis will be used for the subgroup 
analyses. 
a. Subgroup analyses will be conducted using the same model and analysis 
strategies described for the primary and first key secondary analyses but fitted 
by category of each of the subgroups. Subgroup variables that are used as fixed 
effects in the model will be removed from the model statement for the 
subgroup analysis. 
b. Subgroup analysis results will be presented using forest plots. 
 
2.6 
Analysis of the second and third key secondary 
objectives 
2.6.1 
Second and third key secondary endpoints 
The second and third key secondary endpoints are: 


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1. q12 treatmentstatus at Week 48 (for subjects randomized to RTH258 3 mg and 6 mg 
only). 
2. q12 treatment status at Week 48 within the subjects randomized to RTH258 3 mg and 
6 mg, with no q8 need during the first q12 cycle (Week 16 and Week 20), i.e. for how 
many subject was a positive q12- status for the first q12 cycle predictive for the 
adequacy of q12 treatment up to Week 48. 
 
2.6.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis will be tested for the second and third key seconda1y efficacy endpoints. 
The proportion of subjects with  positive  q12  treatment  status  at  Week  48  in  the  
RTH258 treatment aim s overall and within the subjects with no q8 treatment need during the 
first q12 cycle (Week 16 and Week 20) will be presented together with two-sided 95% 
confidence intervals.. 
While for the analysis of the overall q12 proportion, all subjects in the FAS will be considered, the 
analysis of the predictive value of 'no q8-need during the first q12 cycle' is based on the subset of 
FAS subjects with no identified q8-need at Week 16, and Week 20. For this subset a valid Week 
20 diseaseactivity is required while missing the Week 16 assessment is considered as no q8-need. 
During the conduct of the study, confounding effects emerged requirin g consideration to allow for  
a sensitive assessment of the q12 potential ofRTH258. These include the following findings: 
• 
Early treatment / study discontinuation 
• 
Single missed visit 
• 
Forbidden concomitant medications/ procedures 
• 
Discrepancy between the disease activity assessment by masked investigator and the actual 
treatment received  (specifically  over-treatment,  i.e.  switch  to  q8  treatment  without 
identified need. Remark: related under-trnatment is not of concern as the analysis is based 
on the identified q8-need and not on the actual treatment). 
• 
Other treatment allocations /applicationsdeviating from the concept of' disease activity'. 
Following the estimand concept of the study protocol that consequences of lack of efficacy and/or 
lack of safety need adequate reflection in the efficacy estimates, the proportions of patients with a 
positive q12 treatment status will be derived as follows requiring duration of effect (as assessed by 
the q8-need) togetherwith 'sufficient efficacy and safety': 
• 
For the 'duration of effect' requir·ement subjects will need to have the status of ' q8-need = 
no' at all performed disease activity assessments relevant for the coITesponding endpoint 
unless the status 'q8-need =yes' is confounded by reasons other than lack of efficacy and/or 
safety (see censming details below). 
• 
The requiI·ement regarding 'sufficientefficacy and safety' will be addressed by considerin g 
subjects - even without an explicit 'q8-need=yes' - as having a negative q12 status in case 
any of the followmg confounding factors is attiibutable to lack of efficacy and/or lack of 
safety of the study treatment (assessed based on a masked medical review): early 
treatment / study discontinuation, use of forbidden concomitant medications / procedures 
and/or other deviation from treatment schedule ( e.g. due to a missed visit/treatment) . The 
coITesponding q8 -need will be allocated to the next disease activity assessment visit 
(according to protocol) following the occmTence of such a confounding factor. 


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In case the missing or confounded data regarding the q12-status are attributable to reasons other 
than lack of efficacy and/or safety, the subject is censored within the q12-status analysis according 
to the following specifications ( for details see ‘Censoring of DAA’ in the DEP and Section 5.3): 
o Early treatment / study discontinuation: Censoring at the last valid disease activity 
assessment. 
o Single missed visit with a relevant disease activity assessment: Censoring at the 
last valid disease activity assessment prior to the missed visit. 
o Prohibited concomitant medications / procedures: Censoring at the last valid 
disease activity assessment prior to the corresponding application. 
o Discrepancy between disease activity assessment by masked investigator and the 
actual treatment received: Censoring at the visit of the discrepancy (assuming this 
disease activity assessment is valid) 
o Other treatment allocations /applications deviating from the concept of ‘disease 
activity’. Censoring: at the last valid disease activity assessment at or prior to the 
deviation. 
The estimate for the proportion of patients with a positive q12-status at Week 48 will be derived 
from Kaplan Meier time-to-event analyses for the event ‘ first q8-need’ applying event allocations 
(in case of lack of efficacy and/or lack of safety) and censoring as described above. A 
corresponding 95% CI will be derived from the LOGLOG transformation ( see SAS Proc Lifetest, 
CONFTYPE = LOGLOG). 
The outcome of the Kaplan Meier analyses will be presented graphically by the estimated 
q12-probability over time, i.e. at each DAA-visit. 
Remark: Subjects without any relevant valid disease activity assessment are considered censored at 
Baseline for the overall q12-proportion and at Week 20 for the analysis of the predictive value of 
the first q12 cycle. 
 
2.6.3 
Handling of missing values/censoring/discontinuations 
The details regarding handling of missing values and discontinuations including the timing of 
censoring within the time-to-event analyses for the event ‘first q8-need’ are specified above. 
 
2.6.4 
Supportive analyses 
The following supportive analyses will be performed: 
1. ‘ Conservative ’ approach: 
a. For the overall q12-proportion at Week 48, the denominator is the number of FAS 
subjects in the RTH258 3mg/ 6mg groups, and the numerator is the 
corresponding number of subjects with no identified q8-need at Week 16, 20, 
32, and 44 (while missing the Week 20, 32 and/or Week 44 assessment leads 
to an allocation of q8-need as compared to a missing assessment at Week 16 
which is considered as no q8- need at this visit) and no episode of 
overtreatment, i.e. treatments after Week 8 are limited to Week 20, 32 and 44 ( and 
Week 56, 68, 80 and 92 for the Week 96 analysis) . 
 
b. Correspondingly for the q12-proportion at Week 48 in subjects with ‘q8-need 
=no’ during the first q12 cycle (Week 16 and Week 20), the denominator is the 


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Q8 Treatment need as derived from protocol guidance: A 
subject is considered to have a q8 treatment need at a given 
visit if at least one of the corresponding criteria is fulfilled. 
number of FAS subjects in the RTH258 3 mg/6 mg groups with no identified q8- 
need at Week 16 and Week 20 (requiring a valid assessment at Week 20 while 
missing the Week 16 assessment is considered a no q8-need), and the numerator 
being the number of corresponding subjects with a positive q12 treatment status at 
Week 48 i.e. with additionally ‘ q8 need =no’ at Week 32, and 44 and no episode 
of overtreatment (see above). 
 
2. ‘LOCF’ approach: This approach follows in principle the same concepts as described 
above under the ‘conservative’ approach with the difference that the numerator is the 
number of subjects with no identified q8-need and no episode of overtreatment, while only 
the available disease activity assessments are considered, i.e. missing assessments are not 
translated into a q8-need. 
 
3. ‘Efficacy only’ approach: This approach follows the concept of time-to-event analysis 
as described above for the primary analysis approach of the q12-status with the 
difference only requiring ‘sufficient efficacy’, i.e. an allocation of a negative q12- 
status - even without an explicit ‘q8-need=yes’ - in case any of the following confounding 
factors is attributable to lack of efficacy of the study treatment (assessed based on a masked 
medical review): early treatment / study discontinuation, use of prohibited concomitant 
medications / procedures and/or other deviation from treatment schedule ( e.g. due to a 
missed visit/treatment). In case of a corresponding safety reason the subject will be 
censored at the last valid disease activity assessment. 
 
4. The analyses described above for the FAS will be repeated using PPS applying the 
same censoring and imputation concepts. 
5. Subgroup analyses will be conducted to assess the consistency of the q12 proportion 
across various subgroups described in Section 2.2.3. These analysis will be based on 
the Kaplan Meier time-to-event analyses for the event ‘ first q8-need’ as specified in 
section 2.6.2 using the FAS. Subgroup analysis results will be presented by the 
estimated q12-probability over time, i.e. at each DAA-visit and forest plots based on 
the 95% CI of the corresponding Week 48 probability. 
6. Supportive analyses to assess the relationship between the actual investigator decisions 
and the treatment guidance provided in the protocol will be performed using the 
following analyses: 
a. For each DA assessment visit, the number and percentage of subjects who 
according to the treatment guidance have a q8-need (see below) will be 
described separately for those with and without q8 treatment-need as assessed 
by the investigator for all the three treatment arms. For RTH258 subjects, 
separately for the 3mg and 6mg arm, the same analysis will be repeated, but 
only up to and including the first q8 treatment need decision. 
 
 
Visit 


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Week 16 
Decrease in BCVA of ≥ 5 letters compared with Baseline 
Decrease in BCVA of ≥ 3 letters and CSFT increase ≥ 75 μm 
compared with Week 12 
Presence of IRF at Week 16 while absent at Week 12 
Increase in CSFTns of at least 10 microns from Week 12 to Week 
16 (worsening of IRF) 
Decrease in BCVA of ≥ 5 letters from Week 12 AND presence of 
at least one of the following fluids at Week 16: IRF, SRF, and 
subRPE 
Weeks 20, 32, 
and 44 
Decrease in BCVA of ≥ 5 letters from Week 12 AND presence of 
at least one of the following fluids at the relevant visit: IRF, SRF, 
and subRPE 
Weeks 56, 68, 
80, and 92 
Decrease in BCVA of ≥ 5 letters from Week 48 AND presence of 
at least one of the following fluids at the relevant visit: IRF, SRF, 
and subRPE 
b. For RTH258 subjects (separately for the 3mg and 6mg arm) who were 
identified by the investigator as having their first q8-treatment need after 
Week 20, their status regarding the treatment guidance criteria at Week 16 and 
Week 20 will be presented. For this analysis, the number of subjects who 
met/did not meet the treatment guidance criteria at Week 16 and Week 20 will 
be presented in a cross tabulation. 
c. For subjects on q12 treatment at Week 48 and who lost 5 letters or more from 
Week 12 to Week 48, the treatment guidance status at each of the DA 
assessment visits will be presented. For this analysis, the number of subjects 
for each of the patterns of the treatment guidance status at Weeks 16, 20, 32, 
and 44 will be presented in a summary table similar to the one shown below: 
 
Week 
16 
20 
32 
44 
n (%) 
Patterns 
n 
n 
n 
n 
xx (xx.x%) 
p 
n 
n 
n 
xx(xx.x%) 
… 
… 
… 
… 
… 
.. 
Total 
N (100%) 
Treatment guidance status: n= negative status, p=positive status 
 
7. Comparison of new q8-treatment need during RTH258 q12 cycles and Eylea q8 cycles 
 
a. Quantitative comparison of new q8 needs identified at 12 week-assessments for 
RTH58 subjects versus 4 and 8 week-assessments for Eylea 
For each q12-cycle, the proportion of RTH258 subjects (relative to the subjects still on q12 
and separately for the 3mg and 6mg arm) with a newly identified q8-need 12 weeks after the 
last injection will be compared to those Eylea subjects where a new q8 treatment need is 


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identified4-weeks or 8 weeks from the last injection. The following fo1mat will be used to 
present theresult: 
 
RTH258 
q12- 
cycle 
RTH258 (separately for the 3mg and 
6mg arm) 
Eylea 
Disease 
activity 
assessment 
vi sit 
Number 
of 
subjects 
at risk 
New q8-need 
after 12 weeks 
since last 
treatme nt. 
Disease 
activity 
assessment 
vi sit 
Time 
since last 
treatment 
Number 
of 
subjects 
at risk 
New q8-need 
after 4/8 weeks 
since last visit. 
Week 20 
- Week 
32 
Week 32 
(last 
treatment 
Week 20) 
N = 
number 
of 
patient 
011q12 
at Week 
K1, 
( 100*ki/ N %) 
Wee k 32 
(last 
treatment 
Week 24) 
8 wee ks 
N=nmn ber 
of patients 
011 ' q12' 
(=wo q8- 
need) at 
week 20 
K1. 
( 100* k;IN %) 
20 
Week 32 
- Week 
44 
Week 44 
(last 
treatment 
week 32) 
N = 
number 
of 
patient 
on q12 
at Week 
32 
K2, 
( 100*k2,/N %) 
Week 4 4 
(last 
treatment 
week 40) 
4 wee ks 
N =num ber 
of patients 
011 ' q12' 
(=wo q8- 
need) at 
week 40 
K 2. 
( 100*k2.IN %) 
... . 
... . 
... . 
.... 
.... 
.... 
.... 
Week 80 Week 92 
N = 
number 
of 
patient 
0 11q12 
at Week 
80 
r 
Week 92 
8 weeks 
N=number 
- Week 
92 
(last 
treatment 
( 100* ,/N %) 
(last 
treatment 
of patients 
on ' q12' 
( 100*4/N %) 
week 80) 
week 84) 
(=wo q8- 
need) at 
week 80 
Where Kir = n l.llllber of RTH258 subjects with new Q8-need after 8 weeks since last treatment on the ith ql 2 cycle; 
Kie = numbe r of Eylea su bject s w ith new Q8 -need afte r 4 week s sin ce last tI·eatment dtuing the ith RTH258 ql2 
cycle 
b. Qualitative comparison of the disease activity between treatments regarding subjects 
with a new q8 need identified at 12 week-assessments for RTH58 subjects versus 4 / 8 
week-assessments for Eylea 
For the cohorts Krr, Kie, i= l ,..,6 (se e a bove), the number and percentage of subjects with a 
positive disease activity status DA  assessed  according  to  the treatment  guidance  criteria  given 
in Section 2.6.4 will be presented. 
 
2.7 
Analysis of additional secondary efficacy objective(s) 
 
2.7 .1 Se cond ary endpoint s 
The seconda1y endpoints are: 
• Change in BCVA from Baseline to each postbaseline visit 


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• 
Average change in BCVA from Baseline over the period Week 84 through Week 96. 
For each subject this endpoint is derived  as the average of the changes from Baseline 
to Weeks 84, 88, 92 and 96 
• 
Average change in BCVA from Baseline over the period Week 4 to Week 48. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline up to Weeks 48 
• 
Average change in BCVA from Baseline over the period Week 4 to Week  96. For  
each subject this endpoint is derived as the average of the monthly changes from 
Baseline up to Weeks 96 
• 
Average change in BCVA from Baseline over the period Week 12 to Week 48. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline to Weeks 12 up to week 48 
• 
Average change in BCVA from Baseline over the period Week 12 to Week 96. For 
each subject this endpoint is derived as the average of the monthly changes from 
Baseline to Weeks 12 up to Week 96 
• 
Number and percentage of subjects with a gain in BCVA from Baseline to each 
postbaseline visit will be presented for the followingcriteria: 
o 2':15 - letter gain 
o 2':10 -le tter gain 
o 2':5-letter gain 
o Note: Subjects with BCVA value of 84 letters or more at a postbaseline visit 
will be considered as responders for the conesponding endpoint. This is to 
account for a ceiling effect, e.g. for the' 2':15 -l etter ga in' endpoint, for those 
subjects with BCVA values at baseline >= 70 letters. 
• 
Number and percentage of subjects with BCVA of 73 letters or more at each 
postbaseline visit 
• 
Number and percentage of subjects with a loss in BCVA from Baseline to each 
postbaseline visit will be presentedfor the followingcriteria: 
o 2':15 -letter loss 
o 2':10-letterloss 
o 2':5- letter loss 
• 
q12 treatment status at Week 96 (for subjects randomized to RTH258 3 mg and 6 mg 
only). This endpoint is analyzed using the KM method as given for the conesponding 
Week 48 endpoint. 
• q12 treatment status at Week 96 within the subjects with no q8 need during the 1st q12 
cycle (Week 16, Week 20) for subjects randomized to RTH258 3 mg and 6 mg only. 
This endpoint is analyzed using the KM method as given for the conesponding Week 
48 endpoint. 
• 
Number and percent of subjects with q8 treatment need at Weeks 16. 


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• 
Change in CSFT from Baseline to each postbaseline visit 
• 
Average change in CSFT from Baseline over the period Week 36 through Week 48 
• 
Average change in CSFT from Baseline over the period Week 84 through Week 96 
• 
Average change in CSFT from Baseline over the period Week 4 to Week 48 
• 
Average change in CSFT from Baseline over the period Week 4 to Week 96 
• 
Change in CSFTns from Baseline to each postbaseline visit 
• 
Average change in CSFTns from Baseline over the period Week 36 through Week 48 
• 
Average change in CSFTns from Baseline over the Week 84 through Week 96 
• 
Average change in CSFTns from Baseline over the period Week 12 through Week 48 
• 
Average change in CSFTns from Baseline over the period Week 12 through Week 96 
• 
Change in area of CNV within the lesion (CNV lesion size) from Baseline to Weeks 
12, 48 and 96 
• 
Number and percent of subjects with presence of subretinal fluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with presence of intraretinal fluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with presence of sub RPE fluid (central subfield) at 
each postbaseline visit. 
• 
Number and percent of subjects with simultaneous absence of subretinal and 
intraretinal fluid (central subfield) at each postbaseline visit. 
• 
Number of subjects with presence of subretinal hemonhage (central subfield) at each 
assessment visit 
• 
Number of subjects with presence of intraretinal hemonhage (central subfield) at each 
assessment visit 
• 
 Number of subjects with simultaneous absence of subretinal and intraretinal 
hemonhage (central subfield) at each assessment visit 
• 
Number of visits with simultaneous absence of subretinal and intraretinal fluid (central 
subfield during Week 36 to Week 48 
• 
Change in patient-repo1ted outcomes (VFQ-25) total and subscale scores from 
Baseline to Weeks 24, 48, 72 and 96. 
 


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2.7.3 
Statistical hypothesis, model, and method of analysis 
 
2.7.3.1 
Confirmatory testing related to additional secondary endpoints 
Confirmatory hypothesis testing for additional secondary endpoints will be performed in case 
the proof of non-inferiority related to BCVA is successful for all 4 hypotheses specified above 
for the primary and key secondary endpoints. 
The additional efficacy hypotheses are arranged in three sets (A-C) each linked to a different 
efficacy parameter containing a list of related endpoints to be tested for both RTH258 6mg 
and 3mg in comparison to aflibercept: 
 
A. CSFT: 
1. Change in CSFTtot from Baseline to Week 16, 6mg 
2. Change in CSFTtot from Baseline to Week 48, 6mg 
3. Average change in CSFTtot from Baseline over the period Week 36 through Week 
48, 6mg 
4. Change in CSFTtot from Baseline Week 16, 3mg 
5. Change in CSFTtot from Baseline to Week 48, 3mg 
6. Average change in CSFTtot from Baseline over the period Week 36 through Week 
48, 3mg 


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B. Fluid-status ‘yes/no’ ( no= absence of SRF and IRF): 
1. Fluid at Week 16, 6mg 
2. Fluid at Week 48, 6mg 
3. Number of visits without Fluid during Week 36 to Week 48, 6mg 
4. Fluid at Week 16, 3mg 
5. Fluid at Week 48, 3mg 
6. Number of visits without Fluid during Week 36 to Week 48, 3mg 
 
C. DAA ‘yes/no’ ( yes = q8-need according to investigators disease activity assessment): 
1. DAA  at Week 16, 6mg 
2. DAA  at Week 16, 3mg 
 
All tests will be one-sided testing for superiority of RTH258 vs aflibercept, i.e., 
o for greater reductions in the CSFT change from baseline (ANOVA as specified 
below) with RTH258 
o for a higher proportion of subjects with absence of fluid (logistic regression 
with treatment, age categories (<75, ≥75 years) and baseline fluid status as 
fixed effects) with RTH258 
o for higher numbers of visits without fluid (CMH-test row mean score 
(scores=table) stratified by age categories (<75, ≥75 years) and baseline fluid 
status) with RTH258. 
o for a higher proportion of subjects with ‘no q8-need’ (logistic regression with 
treatment and age categories (<75, ≥75 years) as fixed effects) with RTH258 
The basis for these tests for superiority will be the FAS with last-observation-carried-forward 
(LOCF) imputation of missing values. 
 
To allow for parallel testing of these three sets the global one-side alpha of 0.025 is split as 
follows: 
o CSFT : 0.005 
o Fluid (combination of SRF and IRF) : 0.01 
o DAA : 0.01. 
Within each set the corresponding hypotheses will be tested hierarchically according to their 
numbering (see above) at the local alpha-level as specified above for each set. Within this 
hierarchical testing approach confirmatory testing of a given hypothesis requires rejection of 
all preceding null hypothesis within the corresponding set and as specified above also the 
rejection of those related to the primary and key secondary endpoints. 
Based on the graphical approach for sequential rejection of multiple test procedures ( see 
Bretz et al , Statist. Med. 2009; 28:586–604 ), once all null-hypotheses related to one set could 
be  rejected the corresponding alpha assigned to this set will be passed with a 50:50 split to  
the two other sets. In case also all null-hypotheses of a second set can be rejected (including 


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the consideration of received alpha-proport ions) the hierarchical testing related to the 
remaining set can be done at the one-sided alpha of 0.025. 
fu this setting the testing of the prima1y and secondary hypotheses will be controlled at the 
global type I enor rate of 0.025. 
 
2.7.3.2 
General analysis specification for secondary 
 
endpoints 
The analysis of seconda1y efficacy endpoints will be based on the FAS with LOCF imputation 
for missing values. For the endpoints of ql 2 status at Week 96, 
incomplete/missing/confounded data will be handled using the same methods as specified for 
the KM analysis for the key seconda1yendpoints ' q12 treatment status at Week 48 for 
subjects randomized to RTH258 3 mg and 6 mg'. Suppo1t ive analyses based on the PPS will 
be perform ed for endpoints related to BCVA and related to the ql 2 status. Additional analyses 
using the PPS will be conducted if the sensitivity analysis for the prima1y efficacy hypothesis 
suggests relevant differences between FAS and PPS results. fu addition, these endpoints will 
also be summarized and presented descriptively. 
a. Continuous endpoints: 
The continuous variables will be summarized using ANOVA models similar to the one 
specified for the prima1y endpoint. Estimates of least square means for each treatment and for 
the treatment differences including 95% confidence inte1v als and p-values for the treatment 
differences will be presented. fu addition, descriptive statistics based on the obse1ved data 
only will be presented by treatment and visit. 
Note: 
• 
For CNV lesion size, lesion type will be added as a class variable and baseline lesion 
size categories (see con esponding subgroup categories) instead of baseline BCVA 
catego1y 
• 
For the ANOVA analysis  of change  in CSFT,  baseline CSFT catego1ies  (< 400, 2  400 
Lm ) will be used instead of baseline BCVA category as a class varia ble 
• 
For the ANOVA analysis of change in nemosensory re tinal thickness, the baseline 
nemosensoiy retinal thickness categories (<250, 2250 µm) will be used instead  of 
BCVA category as a class variable 
• 
Line plots (LSM ± 1 SE) will be presented for all the ' by visit ' analyses 
b. Categorical variables 
Propo1tions and treatment differences in propo1tions along with 95% confidence inte1vals and 
p-values will be presented using a logistic regression with the con esponding baseline status 
and age categories as fixed effects. 
Bar cha1ts will be produced for all the categorical variables. 
For the endpoints related to fluid / hemon hage / - 
status 
o  Shift tables comparing the status at Baseline to each/specified postbaseline visit will be 
presented 


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o For the analysis of presence of fluid by visit, additional analyses will be performed by 
only including subjects where the corresponding fluid was present at Baseline. 
o For the analysis of the endpoint ‘simultaneous absence of subretinal and intraretinal fluid’, 
additional analysis will be performed by only including subjects where the corresponding 
fluids (at least one fluid type is present) were present at Baseline. 
o 95% exact confidence intervals for the risk differences for the Unstratified analyses will 
be based on the Farrington-Manning score statistic. 
 
2.7.4 
Handling of missing values/censoring/discontinuations 
Missing data will be handled using LOCF and observed case analysis (i.e. no imputation). For 
the endpoints of q12 status , incomplete / confounded data will be handled using the same 
method as specified for the KM analysis for the key secondary endpoint, q12 treatment status 
at Week 48. 
 
2.8 
Safety analyses 
There are no formal safety hypotheses in this study. The focus of the safety analysis will be a 
comprehensive descriptive assessment of all the safety endpoints including, shift tables and 
graphical presentation. 
Safety analyses described in this section will be conducted using the safety analysis set on a 
treatment-emergent basis. For treatment-emergent safety analyses, subjects will be analyzed 
according to the actual treatment they received. If a subject received both study treatments, 
then the subject will be analyzed based on the majority of treatments received up to and 
including Week 44. 
In addition to capturing specific safety assessments on the corresponding eCRF pages, 
findings from such assessments that are deemed to be clinically significant by the investigator 
will also be reported as adverse events. For the safety parameters of slit lamp, fundus exam 
and post injection assessments (except for post-injection IOP), data captured on the 
corresponding eCRF pages will be presented in listings only while related clinically relevant 
findings will be part of the overall adverse event analysis. 
Except for imputation of partial dates, no imputation will be done for missing values for all 
safety analyses. 
Ocular and non-ocular findings (e.g. adverse events) will be presented separately. All results 
related to ocular assessments will be presented using data from the study eye only except for 
adverse events where summaries will be presented separately for both the study and fellow 
eyes. 
The primary safety analyses will include all treatment-emergent data, including data collected 
after the subject discontinued study treatment and started alternative anti-VEGF treatment. A 
sensitivity analysis will be conducted in which, for subjects who discontinued treatment but 
continued in the study, with application of alternative anti-VEGF treatment, their safety data 
are censored at the time the subject started alternative anti-VEGF treatment. That is, only 
safety data collected prior to receiving alternative anti-VEGF treatment will be used for these 
analyses. These sensitivity analyses will be specified in the respective endpoint analysis. 


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For listings that present data from a subset of subjects who satisfy a certain criteria at one visit, 
data at all visits will be presented. 
 
2.8.1 
Extent of exposure 
Analysis of extent of exposure is discussed in Section 2.4.1. Based on the SAP, the overall 
number of active and sham injections up to and including Week 48 and Week 96 will be 
presented descriptively (both as continuous and categorical variable). For the categorical 
presentation, the observed frequencies will be presented as the categories. 
The number and percent of subjects who received wrong active treatment will also be 
presented using a shift table for 'as randomized' vs ' as treated' by visit. A listing will be 
provided for patients who received at least once a wrong treatment. 
 
2.8.2 
Adverse events (AEs) 
The definition of Adverse Event (AE) in the study protocol is restricted to events occuning 
after the first treatment exposure, while for this study AEs were collected from the time of 
info1med consent. In this analysis plan, events that staited prior to the subject receiving 
treatment (= prior to day of first injection) are presented separately as pre-treatment adverse 
events. All AEs occuning from when a subject signs info1med consent to when a subject 
exits the study will be accounted for in the repo11ing. Analysis and presentation of AEs 
occmTing during the screening period will be separated from those occmTing during the 
investigational period where a comparative evaluation of treatment-emergent AEs is intended. 
A treatment-emergent AE is an event not present prior to exposure to investigational product 
or any pre-existing event that worsens following exposure to investigational product. The 
period for treatment-emergent AE analysis sta1ts from the first exposure (= first injection) to 
the investigational product until the subject exits the study. 
Summa1ies (counts and percentages) for specific AEs will be presented by system organ class 
(SOC) and prefened te1m (PT) according to the Med.DRA dictiona1y. Ocu lar and non-ocular 
(systemic) AEs will be presented separately. Oculai· AEs will be presented by study and 
fellow eye separately. In addition to an overall presentation of AEs, rep01ts will be generated 
for special classes of AEs such as serious AEs (SAE), AEs resulting in treatment and/or study 
discontinuation, most frequent AEs ( 2 % in any treatment group for each PT), 
investigational product/administration procedure-related AEs, AEs by maximum severity, 
AEs of special interest and AEs of potential relevance to intravitreal anti-VEGF class. 
Subject listings for all AEs, serious AEs, AEs that lead to discontinuation from treatment 
and/or study, and AEs of special interest will be presented. 
A sensitivity analysis excluding AEs that sta1ted after a subject discontinued study treatment 
and sta1ted alternative anti-VEGF treatment will be presented for the overall AE and SAE 
tables. Additionall y, for subjects who discontinue treatment and sta1ted alternative anti-VEGF 
treatment, a separate table (oculai·, and non-oculai-) by SOC and PT for AEs with onset date 
after sta1tof alternative anti-VEGF treatment will be presented. Additionally, for subjects who 
received different active treatments, a separate table by system organ class and PT for AEs 
with onset date after the subject received the non-randomized active treatment will be 
presented. 


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For subjects who were randomized but did not receive an injection, a subject listing will be 
provided that includes all AEs that occun ed at or after the day of randomization until the 
subject discontinued/exited from the study using the All-randomized analysis set. 
A subject listing will be provided for AEs that occur after signing inform ed con se nt but pri o r 
to ex p os ure to investigational product using the All-emolled analysis set. These listings will 
comprise all events occun ing during this period in any subject who consented to pa1t icipate in 
the study. 
The SOCs will be presented in alphabetical order. Prefen ed terms will be ordered within each 
SOC by decreasing incidence in the Brolucizumab 6 mg treatment arm. The MedDRA version 
used for report ing the study will be the latest available prior to the database lock and will be 
described in a footnote. 
Summary tables for in-text prese ntations will be summarized by PT. 
 
2.8.2.1 
Adverse events of special interest (AESls) 
The AESis specified in the protocol are the following: 
• 
Endophthalmitis 
• 
Grade 3 aqueous flare/Grade 4 aqueous cells (see MOP for grading scale) 
• 
Grade 2 aqueous flare/Grade 3 aqueous cells that fails to decrease to 1 or less within 
30 days of the onset of the event (see MOP for grading scale) 
• 
30 letter decrease in BCVA compared with Baseline visual acuity 
• 
Sustained (> 15 minutes) loss of light perception due to elevated IOP 
• 
IOP > 30 mmHg at/past 60 minutes post-injection 
• 
Any elevation ofI OP requiring surgical intervention(e.g., paracentesis) 
• 
New retinal tear or detachment 
• 
New vitreous hemon hage > 2+ severity that does not resolve within 14 days of the 
onset of the event (see MOP for grading scale) 
• 
New diagnosis of geographic atrophy 
AESis will be identified by the investigator on the AE eCRF page and will be summarized 
using counts and percentages by system organ class and prefen ed term accor ding to the 
MedDRA dictionary. A subject listing will also be presented for AESis. 
A sensitivity analysis excluding AESis that start ed after a subject discontinued study 
treatment and started alternative anti-VEGF treatment will be presented for the AESI table. 
Additionally, for subjects who discontinue treatment, a separate table for AESis with onset 
date after start of alternative anti-VEGF treatment will also be presented. 
 
2.8.2.2 
AEs of potential relevance to intravitreal anti-VEGFclass 
Tables and Listings for AEs with potential relevance to the intravitreal anti-VEGF class will 
also be presented, and summarized (counts and percentages) by system organ class and 
prefen ed term according to the MedDRA dictionary. Ocular and non-ocular (syste mic) AEs 


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will be presented separately. Ocular AEs will be presented by study and fellow eye separately. 
These AEs are presented in the table (Table 1) below. 


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Table 1 
AEs of potential relevance to intravitreal anti-VEGF class 
 
 
Safety Topic Of 
Interest 
SOC 
Data 
Domain 
MedDRA 
Code 
MedDRA Term 
MedDRA 
Level 
MedDRA 
Qualifier 
Location* 
Venous 
thromboembolic 
events 
Vascular 
disorders 
MEDDRA 
90000105 
Venous thromboembolic events 
(excl. ocular) [LUCENTIS] (CMQ) 
NMQ1 
NO 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000061 
Central nervous system 
haemorrhages and cerebrovascular 
conditions (SMQ) 
MQ2 
NARROW 
NO, SE, FE 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000043 
Ischaemic heart disease (SMQ) 
MQ1 
NARROW 
NO 
Arterial 
Thromboembolic 
Events 
Vascular 
disorders 
MEDDRA 
20000082 
Embolic and thrombotic events, 
arterial (SMQ) 
MQ2 
NO, SE, FE 
Infectious 
Endophthalmitis 
Infections and 
infestations 
MEDDRA 
90000101 
Infectious endophthalmitis 
[LUCENTIS] (CMQ) 
NMQ1 
NARROW 
SE, FE 
Intraocular pressure 
increase 
Investigations 
MEDDRA 
90001788 
Increased intraocular pressure 
[RETINA] (CMQ) 
NMQ1 
SE, FE 
Traumatic Cataract 
Eye disorders 
MEDDRA 
90001787 
Traumatic cataract [RETINA] (CMQ) 
NMQ1 
SE, FE 
Retinal arterial 
occlusive events 
Eye disorders 
MEDDRA 
90004735 
Retinal artery occlusive events 
[RTH258] (CMQ) 
NMQ1 
SE, FE 
Systemic 
Hypersensitivity 
Immune system 
disorders 
MEDDRA 
20000214 
Hypersensitivity (SMQ) 
MQ1 
NARROW 
NO 
Non-ocular 
haemorrhage 
Vascular 
disorders 
MEDDRA 
90000106 
Non-ocular haemorrhages 
[LUCENTIS] (CMQ) 
NMQ1 
NO 
Systemic hypertension 
Vascular 
disorders 
MEDDRA 
20000147 
Hypertension (SMQ) 
MQ1 
NARROW 
NO 
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Safety Topic Of 
Interest 
SOC 
Data 
Domain 
MedDRA 
Code 
MedDRA Term 
MedDRA 
Level 
MedDRA 
Qualifier 
Location* 
Glaucoma 
Eye disorders 
MEDDRA 
90001789 
Glaucoma without IOP [RETINA] 
(CMQ) 
NMQ1 
SE, FE 
Vitreous haemorrhage 
Eye disorders 
MEDDRA 
10047655 
Vitreous haemorrhage 
PT 
SE, FE 
Retinal pigment 
epithelial tear 
Eye disorders 
MEDDRA 
10062971 
Retinal pigment epithelial tear 
PT 
SE, FE 
Retinal detachment 
and retinal tear 
Eye disorders 
MEDDRA 
90001746 
Retinal detachment and retinal tear 
[STANDARD] (NMQ) 
NMQ1 
NARROW 
SE, FE 
Intraocular 
inflammation** 
Eye disorders 
MEDDRA 
90004793 
Intraocular inflammation [RTH258] 
(CMQ) 
NMQ1 
SE, FE 
*NO = non-ocular; SE = study eye; FE = fellow eye** Intraocular inflammation AEs will be evaluated in pre-specified sub-categories (Endophthalmitis, 
Anterior Uveitis, Posterior Uveitis, and Other). Preferred terms for these intraocular inflammation sub-categories are presented in Table 9. 
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2.8.3 
Deaths 
All deaths that occurred during the treatment period will be identified on the AE eCRF page 
and will be summarized using counts and percentages by system organ class and preferred 
term according to the MedDRA dictionary. A subject listing will be presented for all deaths 
including date and cause of death. 
 
2.8.4 
Laboratory data 
Clinical laboratory evaluations consist of hematology, blood chemistry and urinalysis. 
Hematology (Complete Blood Count) 
The following hematology parameters will be collected: hematocrit, hemoglobin, red blood 
cell (RBC) count, white blood cell (WBC) count with differential (absolute and percentage of 
neutrophils, lymphocytes, monocytes, eosinophils and basophils) and quantitative platelet 
count. 
Observed values and change from baseline values for each hematology parameter will be 
presented descriptively by visit and treatment group. In addition, descriptive summaries will 
be presented graphically using boxplots. For the parameters presented in Table 2, each value 
will be categorized as low, normal or high using the clinically notable ranges as given in the 
table. A shift table showing category of each parameter at baseline relative to each post- 
baseline visit, to the last assessment, to the most extreme increase and most extreme decrease 
will be presented by treatment group. 
The number and percent of subjects satisfying the liver event / liver laboratory trigger criteria 
shown in Table 3 will also be presented by visit. 


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A subject listing will be provided for all laboratory data collected. Additional listings for 
subjects with at least one value satisfying the clinically notable criteria given on Table 2 and 
the liver event or liver laboratory triggers given on Table 3 will be presented. 
Blood Chemistry 
The following blood chemistry parameters will be collected: blood urea nitrogen (BUN), 
serum creatinine, BUN/creatinine ratio, uric acid, cholesterol, triglycerides, albumin, total 
globulin, A/G ratio, total serum iron, total protein, serum electrolytes (sodium, potassium, 
bicarbonate, chloride, calcium, magnesium), phosphorus, glucose and the following liver 
function tests (LFT): serum aspartate transaminase [AST (SGOT)], serum alanine 
transaminase [ALT (SPGT)], alkaline phosphatase, gamma glutamyl transaminase (GGT), 
total bilirubin, direct bilirubin, indirect bilirubin and lactate dehydrogenase (LDH). 
The blood chemistry parameters will be analyzed and presented in the same manner as the 
hematology variables. 
Urinalysis 
The following urinalysis parameters will be collected: specific gravity, pH, color, protein, 
glucose, blood, ketones, bilirubin and microscopic examination (WBC, RBC, epithelial cells, 
bacteria, mucus, casts and crystals). 
Two of the urinalysis variables (specific gravity and reaction pH) are continuous variables and 
will be presented in the same manner as the hematology and chemistry variables. Specific 
gravity will be represented with 3 decimal places. The remaining variables are categorical and 
will be presented in shift tables as described above. 


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Table 2 
Clinically notable laboratory values 
 
Panel/Test 
Type 
Gende 
r/Age 
Conven 
tional 
Unit 
Conven 
tional 
Low 
Conven 
tional 
High 
SI Unit 
SI 
Lo 
w 
SI 
Hig 
h 
Non- 
numeric 
Chemistry/ 
Calcium 
alert 
All 
mg/dL 
6.1 
12.9 
mmol/L 
1.52 
3.22 
Chemistry/ 
Creatinine 
alert 
All 
mg/dL 
0.7 
1.4 
micro 
mol/L 
62 
124 
Chemistry/ 
Glucose (non 
fasting) 
alert 
All 
mg/dL 
40 
450 
mmol/L 
2.22 
24.98 
Chemistry/ 
Potassium 
alert 
All 
mEq/L 
2.8 
6.3 
mmol/L 
2.8 
6.3 
Chemistry/ 
Sodium 
alert 
All 
mEq/L 
117 
160 
mmol/L 
117 
160 
HCG 
alert 
All 
Negative, 
inconclusi 
ve 
Hematology/ 
Hematocrit 
alert 
All 
% 
18 
60 
% 
18 
60 
Hematology/ 
Hemoglobin 
alert 
All 
g/dL 
8 
22 
g/L 
80 
220 
Hematology/ 
Platelet 
alert 
All 
K/cu mm 
30 
900 
x10^9/L 
30 
900 
Hematology/ 
WBC 
alert 
All 
K/cu mm 
2 
25 
x10^9/L 
2 
25 


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Table 3 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
3 x ULN < ALT/AST ≤ 5 x ULN 
1.5 x ULN <TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST >5 × ULN 
ALP >2 × ULN (in the absence of known bone pathology) 
TBL >2 × ULN (in the absence of known Gilbert syndrome) 
Potential Hy’s Law cases (defined as ALT or AST >3 × ULN and 
TBL >2 × ULN [mainly conjugated fraction] without notable increase in 
ALP to >2× ULN) 
Any clinical event of jaundice (or equivalent term)* 
ALT or AST >3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia** 
Any adverse event potentially indicative of a liver toxicity*** 
* 
AE based on clinical judgement and the lab parameter of total bilirubin (TBL). 
** 
The Lab time of ALT/AST detection has to be within the start and end date of any of the AEs. 
The PTs for these events are: Malaise, Fatigue, Abdominal pain, Nausea, Vomiting, Drug 
reaction with eosinophilia and systemic symptoms, Eosinophilic cellulitis, Allergic 
eosinophilia. 
*** 
These events cover the following (broad clinical terms for hepatic illnesses): hepatic failure, 
fibrosis and cirrhosis, and other liver damage related conditions; non-infectious hepatitis; 
benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
 
2.8.5 
Other safety data 
 
2.8.5.1 
Loss in BCVA 
Counts and percentages of subjects with a predefined decrease in BCVA from Baseline to 
each post-baseline visits, to the last assessment and maximum loss from Baseline to any post- 
baseline assessment visit will be presented for the following cut off points: ≥10-letter loss, 
≥15-letter loss ≥30-letter loss. 
A listing of all subjects with a ≥15-letter loss in BCVA from baseline to any post-baseline 
visit will be presented. For subjects who had ≥15-letter loss at any visit, BCVA values at all 
visits will be presented. 
 
2.8.5.2 
Intraocular pressure 
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the 
nearest whole number. 
Descriptive summaries of pre-injection observed values and change from baseline IOP values 
will be presented at each study visit by treatment. Line plots of the mean change in IOP values 


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with error bars representing ± standard error by visit and treatment will be presented. The x- 
 
 
axis will be study visit and the y-axis will be the change from Baseline value. 
A summary table with counts and percentages of subjects with observed IOP of >30 mmHg 
will be presented separately for pre- and post-injection by visit. In addition, counts and 
percentages of subjects with IOP >30 mmHg at the last assessment and at any postbaseline 
visit will be presented. 
A summary table with counts and percentages of subjects with observed pre-IOP ≥21 mmHg 
in 3 consecutive scheduled visits will also be presented. 
A subject listing of all IOP measurements will be pressed by visit. In addition, a 
listing of all subjects with observed IOP of more than 30 mmHg at any visit will be 
presented. For subjects with observed IOP >30 mmHg at any visit, IOP values at all 
visits will be presented. 
 
2.8.5.3 
Vital signs 
Descriptive summaries of observed values and change from baseline in each vital sign 
parameters at each study visit will be presented. 
A summary table with counts and percentage of subjects satisfying the criteria given in Table 
4 will be presented by visit, to the last assessment visit and to at least one visit. 
 
Table 4 
Clinically notable changes in vital signs 
 
Variable 
Category 
Critical Values 
Systolic blood 
pressure (mmHg) 
High 
Either >180 with an increase from baseline >30 or >200 
absolute 
Low 
Either <90 with a decrease from baseline >30 or 
<75 absolute 
Diastolic blood 
pressure (mmHg) 
High 
Either >105 with an increase from baseline >20 or >115 
absolute 
Low 
Either <50 with a decrease from baseline > 20 or 
<40 absolute 
Pulse rate (bpm) 
High 
Either >120 with an increase from baseline of >25 or > 130 
absolute 
Low 
Either <50 with a decrease from baseline >30 or 
<40 absolute 
A line plot of mean change from baseline in the vital sign parameter by study visit and 
treatment with error bars representing ±1 standard error will be presented. The x-axis will be 
study visit and the y-axis will be the mean change from baseline value. 
A subject listing of all vital sign parameters will be presented. In addition, a separate listing 
for subjects satisfying at least one criterion in Table 4 will also be presented. 
 
2.8.5.4 
Slit Lamp examination 
A slit-lamp examination will be performed to evaluate the anterior segment of the eye, 
including lid/lashes, conjunctiva, cornea, lens, iris, aqueous cells and aqueous flare. All data 
collected on the corresponding eCRF page will be presented in a subject listing. 


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2.8.5.5 
Fundus examination 
Fundus examination will be performed to evaluate the health of the retina, macula, choroid, 
optic nerve, and vitreous. The retina will also be assessed for retinal detachment/tear and 
hemorrhage and the vitreous will be evaluated for hemorrhage and vitreal cells. All data 
collected on the fundus exam eCRF page will be presented in a subject listing. 
 
2.8.6 
Presence of geographic atrophy 
Shift tables comparing Baseline vs post baseline values for presence of geographic atrophy 
(central subfield) from color fundus photography, as graded by the central reading center, will 
be presented. In addition, shift tables comparing the Baseline value to the last assessment visit, 
and to any visit with a presence of geographic atrophy will also be presented. Geographic 
atrophy will also be assessed based on presence (shift tables) and area of atrophy (descriptive 
statistics) on fundus autofluorescence within the subset of sites which provided these data. 
 
2.8.7 
Post-injection assessment 
Post-injection parameters to be evaluated in the study eye are gross assessment of vision, the 
status of the central retinal artery, presence of retinal detachment, new intraocular 
hemorrhage(s) and IOP. 
A summary table with counts and percentage of subjects with IOP increase of ≥10, ≥20 
mmHg from pre-injection to post-injection will be presented by visit, at the last visit, and at 
any visit. IOP assessment done at 30 (±15) minutes post-injection will be used for this 
analysis. Separate summaries will be presented for active and sham injections. 
The difference in the pre-and post-injection IOP values will be presented descriptively by 
treatment and visit. Separate summaries will be presented for active and sham injections. 
A listing for subjects with post-injection IOP increase of ≥10 mmHg from pre-injection IOP 
will also be presented. 
All other post-injection assessment data collected on the eCRF will be presented in subject 
listings. 
 
2.8.8 
Presence of anti-drug antibody (ADA) 
Blood samples to test for serum anti-drug antibody (ADA) will be collected following pre- 
determined sample collection time points. Number and percent of subjects according to their 
ADA status (ADA negative, ADA positive without boost, induced, boosted) will be presented 
by treatment and by intraocular inflammation AE status (Table 9). In addition, ADA titer 
pattern and shift table showing ADA titer at baseline relative to each post-baseline assessment 
visit, relative to the last assessment visit, and to any visit with most extreme increase in ADA 
titer will be presented by treatment. Subject listing of all ADA titer values will be presented 
for all subjects and separately for subjects with an intraocular inflammation AE. 
Patient profile plots (including both efficacy and safety endpoints) will be presented for 
subjects with ADA status ‘induced’ and/or ‘boosted’. The visits where a positive ADA result 
is confirmed will be shown on the subject profile plot. 
ADA data up to Week 36 will be analyzed for the Week 48 primary analysis. The final Week 
96 analysis will include all ADA data. 


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2.9 
Pharmacokinetic endpoints 
A subject listing will be provided for all subjects that have detectable RTH258 sernm 
concentration value at any of the PK assessment visits. 
For each assessment time-point, the mean RTH258 serum concentration will be provided 
together with the percentage of subjects with a detectable con esponding concentration level. 
For the assessment visits after Week 12 theses presentations will be categorized by the time 
since last injection of RTH258 (categories: 4/8/12 weeks). 
 
2.10 
Subject-reported outcome 
2.10.1 
Visual function questionnaire (VFQ-25) 
Each subscale score has a range of 0 to 100 inclusive and will be calculated from the 
re-scaled raw data as described in Table 5. A missing response will not be re-scaled 
(except for the response to question 15c, see below, which will be re-set to 0 if the 
response to question15b is 1). 
The answers to questions will be re-scaled as follows to calculate the total and 
subscale scores. 
 
Table 5 
Rescaling of VFQ-25 questions 
Answer to 
question 
Rescaling for 
questions 1, 3, 4 
and 15c 
Rescaling for 
question 2 
Rescaling for 
questions 5 - 14, 
16 and 16a 
Rescaling for - 
questions 17 - 
25 
1 
100 
100 
100 
0 
2 
75 
80 
75 
25 
3 
50 
60 
50 
50 
4 
25 
40 
25 
75 
5 
0 
20 
0 
100 
6 
NA 
0 
NA 
NIA 
 
• Note that the answer to question 15c will subsequently be adjusted based on the 
answer to question 15b. 
• 
If the answer to 15b is 1 then the answer to 15c will be re-set to 0. 
• If the answer to 15b is 2 or 3 then the answer to 15c will be re-set to missing 
The general health rating is the re-scaled answer to question1. 
Response choice "6" indicates that the person does not perform the activity because 
of non-vision related problems. If this choice is selected, the item is coded as 
"missing". Subscales will  be calculated where at least one  of  the  (re-scaled) 
questions contributing to that subscale is non-missing, and otherw ise se t to missing. 
The scales and co1Tesp o ndin g q uestions are shown in Table 6. 


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Table 6 
Questions contributing to VFQ subscales 
 
Subscale 
Questions 
General vision 
2 
Ocular pain 
4 and 19 
Near activities 
5, 6 and 7 
Distance activities 
8, 9 and 14 
Social functioning 
11 and 13 
Mental health 
3, 21, 22 and 25 
Role difficulties 
17 and 18 
Dependency 
20, 23 and 24 
Driving 
15c, 16 and 16a 
Color vision 
12 
Peripheral vision 
10 
 
The composite score is the average of the 11 subscales shown in Table 6. It will be set to 
missing if at least six of the subscales are missing. 
Descriptive summary statistics for rescaled values and change from baseline to post baseline 
VFQ assessment visits will be presented using the full analysis set for the composite and 
subscale scores. Mean changes from baseline to each post baseline VFQ assessments visits 
will be compared between the study treatment groups and the control group. Appropriate 
statistical methods (CMH or ANCOVA Model with treatment and the corresponding baseline 
value in the model) will be used for treatment group comparisons. Additionally, descriptive 
statistics will also be presented for the general health score. All analysis will be done on the 
rescaled values. The change from baseline will derived based the changes in the individual 
items scores and then averaged for the subscale score. 
The VFQ-25 composite score and subscale scores will also be presented in a subject listing. 
 
2.11 
Interim analysis 
No interim analysis prior to the primary analysis at Week 48 is planned for this study. 
 
3 
Sample size calculation 
A sample size of 297 subjects per treatment arm is sufficient to demonstrate noninferiority 
(margin = 4 letters) of RTH258 3 mg/6 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 (990 total). 


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4 
Change to protocol specified analyses 
 
 
TI1e following additional seconda1y 
endpoints that were not specified in the 
protocol were added to this statistical analysis plan. 
• 
• 
• 
• 
Number and percentage of subjects with BCVA of 73 letters or more at each 
postbaseline visit 
• 
 
• 
Average change in CSFTtot from Baseline over the period Week 4 to Week 48/96 
• 
Average change in CSFTtot from Baseline over the period Week 12 through Week 
48/96 
• 
Average change in CSFTtot from Baseline over the period Week 36 through Week 48/ 
over the period Week 84 through Week 96 
• 
Average change in CSFTns from Baseline over the period Week 36 through Week 48/ 
Week 84 through Week 96 
• 
Average change in CSFTns from Baseline over the pe1iod Week 12 through Week 
48/96 
• 
Presence or absence of subretinal and intraretinal (central subfield) hemonhage 
• 
Number of visits with simultaneous absence of subretinal and intraretinal fluid (central 
subfield during Week 36 to Week 48 
• 
 
The followingsubgroups of interest were added: 
• 
Baseline fluid status (IRF, SRF, sub-RPE) 
• 
CNV lesion size 
Following additional safety endpoint that were not specified in the protocol were added to this 
statistical analysis plan 
• 
Presence of geographic atrophy from color fundus photography 


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5 
Appendix 
 
 
 
5.1 
Imputation rules 
5.1.1 
AE date imputation 
 
5.1.1.1 
Adverse event end date imputation 
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the ( 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date. 
 
5.1.1.2 
Adverse event start date imputation 
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed. 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
 
 
The following matrix explains the logic behind the imputation. 
 
 
MON MISSING MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
(1) 
No convention 
(1) 
No convention 
(1) 
No convention 
(1) 
No convention 
YYYY < TRTY (2.a) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
YYYY = TRTY (4.a) 
Uncertain 
(4.b ) 
Before 
Treatment Start 
(4.c) 
Uncertain 
(4.c) 
After Treatment 
Start 
YYYY > TRTY (3.a) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
 
Before imputing AE start date, find the AE start reference date. 


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1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
 
 
start date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Impute AE start date - 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set  
to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date. 
 
5.1.2 
Concomitant medication date imputation 
 
5.1.2.1 
Concomitant medication (CM) end date imputation 
1. If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM 
end date is set to NULL. 
2. Else, if the CM end date month is missing, the imputed end date should be set to the 
earliest of the (treatment end date, 31DECYYYY, date of death). 
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the 
(treatment end date, last day of the month, date of death). 


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If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
 
 
imputed CM end date. 
 
5.1.2.2 
Concomitant medication start date imputation 
In order to classify a medication as prior and prior/concomitant, it may be necessary 
to impute the start date. 
Completely missing start dates will be set to one day prior to treatment start date. As  
a conservative approach, such treatments will be classified as prior and concomitant 
(and summarized for each output). 
Concomitant treatments with partial start dates will have the date or dates imputed. 
The following table explains the notation used in the logic matrix 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY 
TRTY 
< 2.a ) 
Before Treatment 
Start 
2.b ) 
Before Treatment 
Start 
2.b) 
Before Treatment 
Start 
2.b ) 
Before Treatment 
Start 
YYYY 
TRTY 
= 4.a ) 
Uncertain 
4.b ) 
Before Treatment 
Start 
4.a ) 
Uncertain 
(4.c) 
After 
Start 
Treatment 
YYYY 
TRTY 
> (3.a) 
After 
Start 
Treatment 
(3.b) 
After 
Start 
Treatment 
(3.b) 
After 
Start 
Treatment 
3.b) 
After 
Start 
Treatment 
 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid- 
month point (15MONYYYY). 


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3. If the CM sta1t date year value is greater than the treatment stali date year value, the CM 
 
 
stalied after treatment. Therefore: 
a. If the CM month is missing, the imputed CM sta1t date is set to the year start point 
(0lJ anYYYY). 
b. Else if the CM month is not missing, the imputed CM sta1t date is set to the month 
stait point (0l MONYYYY). 
4. If the CM stait date yeai·va lue is equal to the treatment stait date year value: 
a. And the CM month is missing or the CM month is equal to the treatment sta1t date 
month, then the imputed CM stait date is set to one day prior to treatment sta1t date. 
b. Else if the CM month is less than the treatment sta1t date month, the imputed CM statt 
date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment stait date month, the imputed CM 
stait date is set to the month sta1t point (0lMONYYYY). 
If complete (imputed) CM end date is available and the imputed CM sta1t date is greater than 
the (imputed) CM end date, then imputed CM sta1t date should be set to the (imputed) CM 
end date. 
 
5.1 _2.3 Medical history date of diagnosis imputation 
Compl etely missing dates and partially missing end dates will not be imputed. Pa1t ial dates of 
diagnosis will be compai·ed to the treatment start date. 
• 
If DIAG yeai·< treatment stait date yeai· and DIAG month is missing, the imputed DIAG 
date is set to the mid-yeai· point (Ol JULYYYY) 
• 
else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point (15MONYYYY) 
• 
If DIAG year = treatment sta1t date year 
• 
and (DIAG month is missing OR DIAG month is equal to treatment sta1t month), the 
imputed DIAG date is set to one day before treatment sta1t date 
• 
else if DIAG month < treatment sta1t month, the imputed DIAG date is set to the mid- 
month point (15MON YYYY) 
• 
else if DIAG month > treatment sta1t month => data en or 
If DIAG year > treatment start date year => data enor 
5.2 
Statistical models 
5.2.1 
Primary and first key secondary analysis 
The ANOVA, MMRM and logistic regression models, will be fitted using data from two 
treatments at a time. That is, separate models will be fitted for RTH258 3mg vs Aflibercept 
2mg, and RTH258 6mg vs Aflibercept 2mg. 
 
Analysis of Variance (ANOVA) 
The following ANOVA model will be used for the primaiy and first key seconda1yefficacy 
endpoints: 


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<change from Baseline in BCVA at Week 48> <average change from Baseline in BCVA from 
 
 
Week 36 to Week 48> = intercept + treatment + Baseline BCVA category + age category + 
error. 
The following pseudo SAS code will be used to perform the ANOVA analyses: 
PROC MIXED DATA=<Dataset> order=Internal; 
CLASS <Treatment> <BCVA CAT> <AGE CAT> ; 
MODEL <Chg_VA> = <Treatment> <BCVA CAT> <AGE CAT>/ SOLUTION 
LSMEANS Treatment> / DIFF CL ALPHA = 0.05 OM; 
ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 
Where 
<Chg_VA> = primary/first key secondary efficacy endpoint 
<BCVA CAT> = baseline BCVA category 
<AGE CAT> = age category 
<Treatment>= randomized treatment assignment 
The terms in the brackets are to be adjusted according to the real data set and variable names. 
For the above analysis, the data structure is one record per FAS subject. Data will include all 
subjects in the FAS. 
Mixed Model Repeated Measures (MMRM) 
The following MMRM model will be used for the supportive analysis of the primary and first 
key secondary efficacy variables: 
<change from Baseline in BCVA at Week 48> <average change from Baseline in BCVA from 
Week 36 to Week 48> = intercept + treatment + Baseline BCVA category + age category + 
visit + treatment*visit + error. 
The following pseudo SAS code will be used to perform the MMRM analyses: 
 
PROC MIXED DATA=<Dataset> order=Internal; 
CLASS USUBJID <Treatment> <VISIT> <BCVA CAT> <AGE CAT>; 
MODEL <Chg_VA> = <Treatment> <VISIT> <BCVA CAT> <AGE CAT> 
<VISIT>*<Treatment> 
/ solution DDFM=KENWARDROGER ALPHA=0.05; 
REPEATED <VISIT>/type=UN subject=USUBJID; 
LSMEANS <VISIT>*<Treatment> / DIFF CL ALPHA = 0.05 om; 
ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 


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Note: 
<Chg_VA> = primary/first key secondary efficacy endpoint 
<BCVA CAT> = baseline BCVA category 
<AGE CAT> = age category 
<Treatment> = randomized treatment assignment 
…<VISIT> = ordered visit number 
For the above MMRM analysis, the data structure is one record per FAS subject per 
scheduled visit. The data will include all subjects and have records for all scheduled visits, 
regardless of whether the assessment was missed or not at a given visit. Missing values 
will NOT be imputed using LOCF. Instead, the value will be passed to the model as 
missing. 
 
5.2.2 
Key secondary analysis 
The following pseudo SAS code will be used for the logistic regression analysis 
PROC LOGISTIC DATA= data; 
CLASS <Treatment> (REF = "C" ) <BCVA CAT> <AGE CAT> /PARAM=REF; 
MODEL <RESP> (EVENT = '1') = <Treatment> <AGE CAT> <BCVA CAT> 
/ALPHA = 0.05; 
ODS OUTPUT PARAMETERESTIMATES=parameters; 
ODS OUTPUT ODDSRATIOS= OR; 
RUN; 
where, 
 
 
 
 
 
Note: 
 
 
<RESP> = binomial endpoint. 
<BCVA CAT>= baseline BCVA category 
<AGE CAT> = age category 
<Treatment> = randomized treatment assignment 
o For the above analyses, the data structure is one record per subject and visit. 
o The least square mean estimates obtained from the above model are for the log-odds ratios. 
The estimated difference in proportions and the corresponding 95% confidence intervals 
will be obtained by applying the delta method. The pseudo SAS code to derive the 
treatment difference and 95% CI from the least square mean output of the fitted model  
will be provided in the programming specification document. 


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Subject evaluability and censoring 
 
 
Protocol deviations (PD) and analysis restrictions (AR) considered to be critical for subject 
evaluability regarding the prima1y and key seconda1y endpoints are described in the 
Deviations and Evaluability Plan (DEP) document. 
The definition of PDs is provided in the DEP and follows the concept of major/impo1tant 
protocol deviations as outlined in the Guideline (ICH) E3. 
AR's address limitations in the evaluability which result from missing or confounded data 
with underlying background not qualifying as a PD ( e.g. early study terminations, early 
treatment discontinuations, missing visits / missed treatments) 
Subject evaluability is based on two components: 
• 
Exclusion from an analysis set 
• 
Censoling of specific data points from an analysis. 
The consequence of an AR on the evaluability depends on the underlying reason, while three 
different categories of reason are considered: 
• Lack of efficacy of the study treatment (=1) 
• Lack of safety / tolerability of the study treatment (=2) 
• Other (=O) 
R e m ar k: B ase d o n the con cept o f PD ' s, th e ir underl ying reason will always be ' O'. 
As a ge nera l rnle ARs with a reason of 1 or 2 do not lead to an exclusion from any anal ysis set, 
as a potential link between exclusion reason and treatment would constitute a source for a 
systematic bias. 
Table 7 specifies the general criteria leading to exclusion from one or more analysis sets. 
 
Table 7 
Subject Classification 
Analysis Set Criteria that cause subjects to be excluded 
RAN 
Not randomized 
FAS 
Not in the RAN 
Did not receive at least one study in jec ti o n 
PP S 
Not in the FAS 
No valid BCVA assessment during the period Week 36 to Week 48 with 
an underlying reason = 0. 
SAF 
Did not receive at least one study injection 
 
Table 8 summarizes the concepts of censoring for the prima1y parameters BCVAand ql 2- 
status/DAA applied to the two efficacy analysis sets FAS and PPS. The details for the timing 
of censoring for BCVAand DAA are specified in the DEP Table 8-1 in relation to PDs and in 
Table 8-2 in relation to ARs. 


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Table 8 
Censoring concepts for BCVA and DAA within their primary 
analysis approaches 
Analysis Set 
Efficacy 
parameter 
Censoring concept 
FAS 
BCVA 
No censoring related to PDs or ARs. 
Remark: See section 2.5.3 and 2.5.4 for censoring / 
handling of BCVA data afier switch to alternative 
anti-VEGF treatment. 
FAS 
DAA 
The censoring specified in the DEP Tables 8-1 and 
8-2 is applied the same way for FAS and PPS, with 
the option for additional specification in form of 
(FAS:n) in case of PDs / ARs leading to exclusion 
from PPS. 
Remark: The primary analysis of the q12 propo1tion 
as derived from DAA and described in section 2.6.2 
applies censoring in case the underlying DAA is 
considered to be confounded by reasons other than  
1 or 2. Based on the underlying time-to-' first-q8- 
need' anlysis all info1mation up to and including the 
censoring time-point contribute to the evaluation of 
the q12 status. 
PPS 
BCVA 
The censoring specified in the DEP Tables 8-1 and 
8-2 for BCVA is applied 
Remark: Censoring related to switch to standard of 
care is applied in the same was as for the FAS 
PPS 
DAA 
The censoring specified in the DEP Tables 8-1 and 
8-2 for DAA is applied 
 
In case a subject has multiple PDs/ARs with impact on his/her evaluability the following rnles 
are applied: 
 
• 
A subjectis excluded from an analysis set if at least one PD or AR with this 
consequence was identified.This rnle is built on the concept of the medical assessment 
of the 'reason' which considers the reason of an earlier event to potentially also be the 
reason for following PDs or ARs. 
 
• 
In case of multiple censoring time points censoring will be perfom1ed at the earliest. 


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• 
For a single case an adjustmentsof censoring was applied to account for an 
equalization between two PDs/ARs. For details see footnote to DEP Tables 8-1 / 8-2 / 
censoring code ' 6'. 


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Table 9 
Preferred Terms for Intraocular Inflammation 
 
List of PTs: Other 
List of PTs: Anterior Uveitis 
List of PTs: Posterior Uveitis 
List of PTs: Endophthalmitis 
Optic neuritis 
Anterior chamber cell 
Vitritis 
Pseudoendophthalmitis 
Cogan's syndrome 
Anterior chamber fibrin 
Ocular vasculitis 
Non-infectious endophthalmitis 
Idiopathic orbital inflammation 
Ciliary hyperaemia 
Vitreous haze 
Endophthalmitis 
Toxic anterior segment syndrome 
Aqueous fibrin 
Retinitis 
Panophthalmitis 
Uveitis-glaucoma-hyphaema syndrome 
Anterior chamber flare 
Retinal vasculitis 
Acute zonal occult outer retinopathy 
Anterior chamber inflammation 
Noninfective retinitis 
Macular oedema 
Iritis 
Noninfective chorioretinitis 
Oculomucocutaneous syndrome 
Iridocyclitis 
Chorioretinitis 
Periorbital oedema 
Cyclitis 
Choroiditis 
Ocular sarcoidosis 
Cholesterolosis bulbi 
Uveitis 
Birdshot chorioretinopathy 
Cyclitic membrane 
Tubulointerstitial nephritis and uveitis syndrome 
Ophthalmia neonatorum 
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List of PTs: Other 
List of PTs: Anterior Uveitis 
List of PTs: Posterior Uveitis 
List of PTs: Endophthalmitis 
Vogt-Koyanagi-Harada syndrome 
Effe 
Ocular pemphigoid 
ti 
Eye inflammation 
e 
Ocular hyperaemia 
Retinal oedema 
Oculorespiratory syndrome 
Autoimmune uveitis 
Chorioretinopathy 
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Date/Time 
(mm/dd/yyyy GMT): 
Signed by: 
Justification: 
06/12/2017 21:17:43 
Biostats 
06/12/2017 21:53:53 
Management of Affected Area Approval 
 
 
 
 
 
 
 
 
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