A 12-month, Phase IV, Open-label, Randomized, Active Controlled, 2-arm, Multicenter Study Assessing the Efficacy and Safety of Intravitreal Ranibizumab Combined With Grid&Direct Short Pulse Laser Photocoagulation Versus a PRN Ranibizumab Monotherapy in Japanese Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO)
Phase: PHASE4
Conditions: Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO)
Sponsor: Novartis Pharmaceuticals

Medical Division 
Ranibizumab/Lucentis® 
Clinical Trial Protocol [CRFB002EJP09 / NCT02953938] 
A 12-month, phase IV, open-label, randomiZed, actIve 
controlled, 2-arm, multiPle-center study Assessing the 
efficacy and safety of intravitreal raNibizumab combined 
with Grid&Direct short pulse laser photocoagulation versus 
a PRN Ranibizumab monotherapy in Japanese patients 
with macUlar edema secondary to branch retinal vein 
occlusion (BRVO): ZIPANGU study 
Document type: 
Amended Protocol Version 
EUDRACT number: 
NA 
Version number: 
v02 Clean 
Clinical trial phase: 
IV 
Release date: 
21-Jan-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis  
Clinical Trial Protocol Template Version 3.1 (February 2016) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figure ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 7 
Amendment 2 ............................................................................................................................. 9 
Amendment 1 ........................................................................................................................... 10 
Protocol summary .............................................................................................................. 11 
1 
Introduction ....................................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.2 
Purpose .................................................................................................................. 17 
2 
Study objectives and endpoints ......................................................................................... 17 
2.1 
Primary objective ................................................................................................... 17 
2.2 
Secondary objectives ............................................................................................. 17 
 
 17 
3 
Investigational plan ........................................................................................................... 18 
3.1 
Study design .......................................................................................................... 18 
3.2 
Rationale for study design ..................................................................................... 20 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 20 
3.4 
Rationale for choice of comparator ....................................................................... 21 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 21 
3.6 
Risks and benefits .................................................................................................. 21 
4 
Population .......................................................................................................................... 22 
4.1 
Inclusion criteria .................................................................................................... 22 
4.2 
Exclusion criteria ................................................................................................... 22 
5 
Treatment ........................................................................................................................... 25 
5.1 
Study treatment ...................................................................................................... 25 
5.1.1 
Investigational and control drugs .......................................................... 25 
5.1.2 
Additional treatment.............................................................................. 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment and randomization ............................................................. 26 
5.4 
Treatment blinding ................................................................................................ 26 
5.5 
Treating the patient ................................................................................................ 26 
5.5.1 
Patient numbering ................................................................................. 27 
5.5.2 
Dispensing the study drug ..................................................................... 27 
5.5.3 
Handling of study and additional treatment .......................................... 27 

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5.5.4 
Instructions for prescribing and taking study treatment ........................ 28 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 30 
5.5.6 
Rescue medication ................................................................................ 31 
5.5.7 
Concomitant medication ....................................................................... 31 
5.5.8 
Prohibited medication ........................................................................... 31 
5.5.9 
Emergency breaking of assigned treatment code .................................. 32 
5.6 
Study completion and discontinuation .................................................................. 32 
5.6.1 
Study completion and post-study treatment .......................................... 32 
5.6.2 
Discontinuation of study treatment ....................................................... 32 
5.6.3 
Withdrawal of informed consent ........................................................... 33 
5.6.4 
Loss to follow-up .................................................................................. 33 
5.6.5 
Early study termination by the sponsor ................................................. 34 
6 
Visit schedule and assessments ......................................................................................... 34 
6.1 
Information to be collected on screening failures .................................................. 39 
6.2 
Patient demographics/other baseline characteristics ............................................. 39 
6.3 
Treatment exposure and compliance ..................................................................... 39 
6.4 
Efficacy .................................................................................................................. 39 
6.4.1 
Decimal Best-Corrected Visual Acuity ................................................. 40 
6.4.2 
ETDRS Best-Corrected Visual Acuity .................................................. 40 
 
 40 
6.4.4 
Color fundus photography 
 ...................... 40 
 
 41 
 
 41 
 
 41 
6.4.8 
Appropriateness of efficacy assessments .............................................. 41 
6.5 
Safety ..................................................................................................................... 41 
6.5.1 
Ophthalmic examinations...................................................................... 42 
6.5.2 
Vital signs.............................................................................................. 42 
6.5.3 
Height and weight ................................................................................. 42 
6.5.4 
Laboratory evaluations .......................................................................... 42 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 43 
6.5.6 
Pregnancy assessments.......................................................................... 43 
6.5.7 
Appropriateness of safety measurements .............................................. 43 
6.6 
Other assessments .................................................................................................. 43 
6.6.1 
Clinical Outcome Assessments (COAs) ............................................... 43 
6.6.2 
Resource utilization ............................................................................... 43 
6.6.3 
Pharmacokinetics .................................................................................. 43 

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6.6.4 
DNA sampling ...................................................................................... 44 
6.6.5 
Pharmacogenetics .................................................................................. 44 
6.6.6 
Other biomarkers ................................................................................... 44 
7 
Safety monitoring .............................................................................................................. 44 
7.1 
Adverse events ....................................................................................................... 44 
7.2 
Serious adverse events ........................................................................................... 45 
7.2.1 
Definition of SAE ................................................................................. 45 
7.2.2 
SAE reporting........................................................................................ 46 
7.3 
Liver safety monitoring ......................................................................................... 47 
7.4 
Renal safety monitoring ......................................................................................... 47 
7.5 
Reporting of study treatment errors including misuse/abuse ................................ 47 
7.6 
Pregnancy reporting ............................................................................................... 48 
7.7 
Prospective suicidality assessment ........................................................................ 48 
8 
Data review and database management ............................................................................. 48 
8.1 
Site monitoring ...................................................................................................... 48 
8.2 
Data collection ....................................................................................................... 49 
8.3 
Database management and quality control ............................................................ 49 
8.4 
Data Monitoring Committee .................................................................................. 50 
8.5 
Adjudication Committee ........................................................................................ 50 
9 
Data analysis ...................................................................................................................... 50 
9.1 
Analysis sets .......................................................................................................... 50 
9.2 
Patient demographics and other baseline characteristics ....................................... 51 
9.2.1 
Demographics and baseline characteristics ........................................... 51 
9.2.2 
Medical history...................................................................................... 51 
9.3 
Treatments ............................................................................................................. 51 
9.3.1 
Study treatment ..................................................................................... 51 
9.3.2 
Bilateral treatment ................................................................................. 52 
9.3.3 
Prior and concomitant medication ........................................................ 52 
9.4 
Analysis of the primary variable............................................................................ 52 
9.4.1 
Variable ................................................................................................. 52 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 52 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 53 
9.4.4 
Sensitivity analyses ............................................................................... 53 
9.5 
Analysis of secondary variables ............................................................................ 53 
9.5.1 
Efficacy variables .................................................................................. 53 
9.5.2 
Safety variables ..................................................................................... 54 
9.5.3 
Resource utilization ............................................................................... 56 

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9.5.4 
Pharmacokinetics .................................................................................. 56 
9.5.5 
DNA ...................................................................................................... 56 
9.5.6 
Biomarkers ............................................................................................ 56 
9.5.7 
PK/PD ................................................................................................... 56 
 
 56 
9.7 
Interim analyses ..................................................................................................... 57 
9.8 
Sample size calculation.......................................................................................... 57 
10 Ethical considerations ........................................................................................................ 57 
10.1 
Regulatory and ethical compliance ........................................................................ 57 
10.2 
Informed consent procedures ................................................................................. 58 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 58 
10.4 
Publication of study protocol and results............................................................... 58 
10.5 
Quality Control and Quality Assurance ................................................................. 59 
11 Protocol adherence ............................................................................................................ 59 
11.1 
Protocol amendments............................................................................................. 59 
12 References ......................................................................................................................... 59 
13 Appendix 1: Clinically notable vital signs ........................................................................ 62 
14 Appendix 2: Pre-Injection procedures for ranibizumab .................................................... 63 
15 Appendix 3: Post-Injection procedures for ranibizumab Instructions ............................... 64 
16 Appendix 4: Post-treatment procedures for laser photocoagulation ................................. 65 
 
List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 32 
Table 6-1 
Assessment schedule ............................................................................. 35 
Table 7-1  
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 48 
 
List of figure 
Figure 3-1 
Study design .......................................................................................... 19 
 

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List of abbreviations 
AE 
Adverse event 
AMD 
Age-related macular degeneration 
BCVA 
Best-corrected visual acuity 
BRB 
Blood retinal barrier 
BRVO 
Branch retinal vein occlusion 
BSL 
Baseline 
BQA 
Biostatistics Quality Assurance 
CF 
Color fundus photography 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract Research Organization 
CRVO 
Central retinal vein occlusion 
CSFT 
Central subfield thickness 
DAR 
Drug administration record 
DME 
Diabetic macular edema 
DS&E 
Drug Safety and Epidemiology 
eCRF 
electronic Case Report Form 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
 
 
FAS 
Full Analysis Set 
IgG 
Immunoglobulin G 
IOP 
Intraocular pressure 
LOCF 
Last observation carried forward 
 
 
ME 
Macular edema 
MedDRA 
Medical dictionary for regulatory activities 
 
 
PFS 
Prefilled syringes 
PMDA 
Pharmaceutical and Medical Devices Agency 
PMS 
Post marketing surveillance 
PPS 
Per Protocol Set 
PRN 
Pro re nata 
 
 
RVO 
Retinal vein occlusion 
SAE 
Serious adverse event 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
wAMD 
wet age-related macular degeneration 
WHO 
World Health Organization 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Decimal VA 
Visual acuity expressed as a decimal. Best-corrected visual acuity 
will be assessed in a sitting position using Decimal VA testing 
charts at an initial testing distance of 5 meters at every visit. 
Screening 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol). 
Enrollment 
Point/time of patients to be randomized into the study; the point at 
which screening is completed and informed consent has been 
taken (prior to starting any of the procedures described in the 
protocol). 
ETDRS (Early Treatment 
Diabetic Retinopathy Study) 
A National Eye Institute-supported, multicenter, randomized clinical 
trial designed to evaluate photocoagulation and aspirin treatment in 
the management of patients with non-proliferative or early 
proliferative diabetic retinopathy. 
Fellow treated eye  
The fellow treated eye is the non-study eye treated with 
ranibizumab for visual impairment due to macular edema 
secondary to retinal vein occlusion. 
Fellow untreated eye 
The fellow eye that has not been treated with ranibizumab. 
The fellow untreated eye is the non-study eye until treated with 
ranibizumab for visual impairment due to macular edema 
secondary to retinal vein occlusion. After treatment, it becomes the 
fellow treated eye. 
Investigational drug 
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.” 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each patient in the study. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as Screening, Baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study before the planned 
completion of all study drug administration and assessments; at 
this time all study drug administration is discontinued and no further 
assessments are planned. 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study/investigational treatment was discontinued whichever 
is later. 
Study drug 
Any drug administered to the patient or therapeutic procedure as 
part of the required study procedures; includes investigational drug 
and any control drugs or therapeutic procedure. 

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Study eye 
The study eye is the eye selected by the investigator at Baseline 
(according to the protocol) to receive the study treatment. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment 
for any reason; may or may not also be the point/time of premature 
patient withdrawal. 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points. 
 

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Amendment 2 
Amendment rationale  
The purpose of this amendment is to allow temporary use of phenothiazines for common cold 
and upper respiratory infection as mentioned in the below section. 
Study CRFB002EJP09 was initiated on 15-Dec-2016 and enrollment is currently ongoing. As 
of 21-Jan-2018, 59 patients have been randomized in the study. This amendment will not 
impact the study population, drug administration, objectives, endpoints, or study results. 
Changes to the protocol 
Phenothiazine was included as prohibited medication in the final study protocol, as this 
medication is known to be toxic to the lens, retina or optic nerve. However, the symptoms are 
generally thought to occur with long-term use. Therefore, it is reasonable to allow the 
temporary use of phenothiazine with common cold and upper respiratory infection, which has 
been clarified in this amended version. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using red underlined for insertions. Appropriate changes are made in Section 
4.2, Section 5.5.8, and Table 5-1. 
A copy of this amended protocol will be used for Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) submissions. 
The health Authority (HA) submission/notification will be assessed by Post-marketing Study 
Protocol Evaluation Committee (PSPEC) considering local HA requirements. 
The changes herein do not affect the trial specific model ICF. 

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Amendment 1 
Amendment rationale  
The purpose of this amendment is to update and revise clinical chemistry parameters as 
mentioned in the below section. 
This study is in the start-up phase and not enrolled/screened any patients at the time of this 
amendment. This amendment will not impact the study population, drug administration, 
objectives, endpoints, or study results. 
Changes to the protocol 
The clinical chemistry parameters VEGF-A, VEGF-B, and PlGF are replaced with VEGF 
in Table 6-1 footnote (# b) and Section 6.5.4.2. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be used for Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) submissions. 
The health Authority (HA) submission/notification will be assessed by Post-marketing Study 
Protocol Evaluation Committee (PSPEC) considering local HA requirements. 
The changes herein do NOT affect the trial specific model ICF. 

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Protocol summary 
 
Protocol number 
CRFB002EJP09 
Title 
A 12-month, phase IV, open-label, randomized, active controlled, 2-arm, 
multicenter study assessing the efficacy and safety of intravitreal 
Ranibizumab 
combined 
with 
Grid&Direct 
short 
pulse 
laser 
photocoagulation versus a PRN Ranibizumab monotherapy in Japanese 
patients with macular edema secondary to branch retinal vein occlusion  
(BRVO). 
Brief title 
Study to show a superior benefit in terms of reduction of ranibizumab 
injections in patients receiving ranibizumab plus laser photocoagulation 
combination therapy without loss of efficacy and safety.  
Sponsor and Clinical 
Phase 
Novartis Pharma K.K (Phase IV) 
Investigation type 
Drug, Laser photocoagulation 
Study type 
Interventional 
Purpose and rationale 
This study is designed to evaluate comparative efficacy and safety data as 
well as injection frequency data for ranibizumab using a pro re nata (PRN) 
dosing, administered with Grid&Direct short pulse laser photocoagulation 
versus ranibizumab monotherapy using the same dosing up to Month 12 in 
Japanese patients with visual impairment due to macular edema (ME) 
secondary to BRVO. 
Primary Objective 
To demonstrate that PRN regimen (PRN, according to the Japanese label 
of ranibizumab) of ranibizumab combined with Grid&Direct short pulse 
laser photocoagulation reduces the burden of frequent ranibizumab 
injections as compared to ranibizumab monotherapy. The primary objective 
will be assessed by the difference in the mean number of ranibizumab 
injections applied up to Month 11 between the 2 treatment arms. 
Secondary Objectives 
The secondary objectives of this study are as follows: 
• 
To evaluate the efficacy of each arm as assessed by Best-
corrected visual acuity (BCVA) 
• 
To evaluate the efficacy of each arm as assessed by center 
subfield thickness (CSFT) 
• 
To evaluate the safety of ranibizumab monotherapy and 
ranibizumab combined with Grid&Direct short pulse laser 
photocoagulation therapy in Japanese patients as assessed by 
the type, frequency, and severity of ocular and non-ocular adverse 
events (AEs) from Baseline (Day 1) to Month 12 
Study design 
This is a Phase IV, randomized, open-label, active-controlled, 2-arm, 
multicenter study. Patients will be randomized in a 1:1 ratio to 1 of the 2 
treatment arms; i.e. Arm 1 ranibizumab monotherapy, Arm 2 ranibizumab 
with Grid&Direct short pulse laser photocoagulation combination therapy. 
In addition to screening and Baseline (Day 1), there will be monthly visits 
from Month 1 to Month 12. 
There will be 3 periods in this study: Screening Period, Treatment Period 
and Follow-up Period. 
Population 
This study will include male and female patients (≥20 years old) diagnosed 

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with visual impairment due to ME secondary to BRVO. Assuming an 
approximate 20% drop out rate, approximately 70 patients will need to be 
screened to have at least 56 patients found eligible and commencing 
treatment in the trial. 
Key Inclusion criteria 
Key inclusion criteria: 
• 
Written informed consent must be obtained before any assessment is 
performed. 
• 
Male or female patients ≥ 20 years of age. 
• 
Diagnosis of visual impairment exclusively due to ME secondary to 
BRVO. 
• 
Best-corrected visual acuity score at Screening and Baseline (Day 1) 
between 0.5 and 0.05 decimal (i.e., between 73 and 19 letters in Early 
Treatment Diabetic Retinopathy Study (ETDRS) testing) with Landolt C 
charts inclusively (i.e., approximate logarithm of the minimum angle of 
resolution (logMAR) units of 0.3 to 1.30). 
• 
At Baseline (Day1), a maximum BCVA gain of 0.2 units logMAR 
conversion inclusively from screening is allowed as long as the BCVA 
score does not exceed the upper limit of 0.3 units logMAR. 
• 
Increased central subfoveal thickness (> 300 µm at Baseline (Day 1) 
when measured by SD-OCT). 
• 
Duration of vision deterioration ≤6 months (determined by self-report) 
at screening. 
Key Exclusion criteria 
Key exclusion criteria: 
• 
Pregnant or nursing (lactating) women. 
• 
Stroke or myocardial infarction less than 3 months before Screening. 
• 
Uncontrolled blood pressure defined as systolic value of >160 mm Hg 
or diastolic value of >100 mm Hg at Screening or Baseline (Day 1). 
Antihypertensive treatment can be initiated and must be taken for at 
least 30 days after which the patient can be assessed for study 
eligibility a second time. 
• 
Any active periocular or ocular infection or inflammation (e.g., 
blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at 
the time of Screening or Baseline (Day 1) in either eye. 
• 
Uncontrolled glaucoma (intraocular pressure (IOP) ≥30 mm Hg on 
medication or according to investigator’s judgment) at the time of 
Screening or Baseline (Day 1) or diagnosed within 6 months before 
Baseline (Day 1) in either eye. 
• 
Neovascularization of the iris or neovascular glaucoma in the study 
eye. 
• 
Use of any systemic anti-VEGF drugs within 6 months before Baseline 
(Day1) (e.g., sorafenib (Nexavar®), sunitinib (Sutent®), bevacizumab 
(Avastin®), ziv-aflibercept (ZALTRAP®)). 
• 
Treatment (or anticipated treatment in the fellow eye for non-RVO 
indications during the study) with any anti-angiogenic drugs (including 
any anti-VEGF agents) within 3 months before Baseline (Day1) in 
fellow eye or before Baseline (Day 1) in the study eye (e.g., pegaptanib 
(Macugen®), ranibizumab (Lucentis®), bevacizumab (Avastin®), and 
aflibercept (EYLEA®)). 
• 
Panretinal laser photocoagulation within 1 month before Baseline 
(Day1) or anticipated or scheduled within the next 12 months (Study 
periods) following Baseline (Day1) in the study eye. 
• 
Any giving of focal or grid laser photocoagulation before Baseline 

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(Day1) in the study eye. 
• 
Use of intra- or periocular corticosteroids (including sub-Tenon) within 3 
months before Screening in the study eye. 
• 
Any use of intraocular corticosteroid implants (e.g., dexamethasone 
(Ozurdex®), fluocinolone acetonide (Iluvien®)) in the study eye. 
Study treatment 
The investigational treatment used in this study is 0.5 mg ranibizumab 
applied PRN as intravitreal injection of 0.05 mL, with or without Grid&Direct 
short pulse laser photocoagulation treatment. 
Arm 1: Patients will start study treatment with ranibizumab on Baseline 
(Day 1) and having reached stable status (i.e., as per satisfied stabilization 
criteria as mentioned below) ranibizumab treatment may be temporarily 
discontinued. Patients should be monitored monthly for visual acuity (VA) 
and disease activity and ranibizumab injections will be given using PRN 
regimen. The minimum gap required between 2 injections of ranibizumab 
will be 30 ± 7 days. 
Arm 2: Patients will start study treatment with ranibizumab on Baseline 
(Day 1) and having reached stable status, ranibizumab treatment may be 
temporarily discontinued. Patients should be monitored monthly for VA and 
disease activity. Ranibizumab injections are given using PRN regimen. 
Grid&Direct short pulse laser photocoagulation treatment must be applied 
to the target within vascular arcades as soon as indicated. Following the 
complete application of the initial laser treatment, further laser treatment 
can be applied in the presence of ME due to BRVO at the investigator’s 
discretion at minimal intervals of 30 ±7 days. 
PRN (re-treatment/stabilization) criteria: 
After Baseline (Day 1) visit, if any one or more criteria from the below list is 
met, the patient should be administrated ranibizumab treatment (re-
treatment criteria) 
1. Center subfield thickness  ≥ 300 μm 
2. An increase of CSFT ≥ 20% compare to minimum value during the 
treatment period. 
3. The loss of VA due to disease activity secondary to BRVO 
(disease activity includes ME, intra-retinal cysts, sub-retinal fluid, 
macular hemorrhage etc.). This criteria is based on Investigator's 
judgement including the following scenarios: 
• 
The VA is expected to improve if the existing disease activity 
is removed, hence investigator decides to treat with 
ranibizumab  
• 
The VA is expected to be decreasing because of the existing 
disease activity, hence investigator decides to treat with 
ranibizumab  
• 
The VA has decreased as compared to the previous month 
because of the appearance of disease activity, hence 
investigator decides to treat with ranibizumab (This criterion 
is to restart ranibizumab after interruption) 
If all the above criteria are not satisfied, then the patient shouldn’t be 
treated with ranibizumab (stabilization criteria), i.e., 
• 
Center subfield thickness < 300 μm 
• 
An increase of CSFT < 20% compare to minimum value 
during the treatment period 
• 
Visual acuity is stable and the disease activity is in the state 

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of not affecting VA (based on investigator’s judgement) 
Efficacy assessments 
Efficacy assessments will include: 
• 
Decimal and ETDRS Best-Corrected Visual Acuity (BCVA). 
 
 
• 
Color fundus photography (CF) 
 
 
. 
 
. 
 
. 
Key safety 
assessments 
Safety assessments will include the following evaluations: AEs, ophthalmic 
examinations, 
vital 
signs, 
laboratory 
evaluations, 
and 
pregnancy 
assessments. 
Other assessments 
No other assessments will be performed. 
Data analysis 
The primary variable is the mean number of ranibizumab injections applied 
up to Month 11 between the 2 treatment arms in patients with visual 
impairment due to ME secondary to BRVO. 
The statistical hypothesis testing of the number of ranibizumab treatments 
will be based on a stratified Cochran-Mantel-Haenszel (CMH) test. 
Stratification will be done based on categories of baseline decimal VA 
(<0.3, or ≥ 0.3). Difference of mean number of injections, 95% confidence 
interval (CI) of difference and one-sided p-value of the CMH test will be 
reported. 
No imputation is required for the primary endpoint which is number of 
ranibizumab injections, based on PRN regimen. 
Key words 
Macular edema, Branch retinal vein occlusion, best-corrected visual acuity, 
central 
subfield 
thickness, 
pro 
re 
nata, 
ranibizumab, 
laser 
photocoagulation. 

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1 
Introduction 
1.1 
Background  
Retinal vein occlusion (RVO) is the second most common retinal vascular permeability 
disorder after diabetic retinopathy and it is a significant cause of visual handicap (Wong and 
Scott 2010). According to the Hisayama study which is prospective large-scale cohort study in 
Japan, the prevalence of RVO was 2.1% (2.0% for branch RVO (BRVO) and 0.2% for central 
RVO (CRVO)) (Yasuda et al. 2010), and the 9-year incidence of RVO was 3.0% (2.7% for 
BRVO and 0.3% for CRVO) (Arakawa et al. 2011) in Japan. Macular edema (ME) is the 
major complication causing the central vision loss in patients with BRVO or CRVO. ME is 
characterized by swelling of the central part of the retina that mediates high-resolution vision. 
When the area of swelling is located within one disc diameter (approximately 1500 μm) from 
the center of the fovea, vision is likely to be impaired. 
ME arises from breakdown of the blood retinal barrier (BRB), resulting in the pathologic 
accumulation of both fluid and macromolecules in the retina. The breakdown of the BRB may 
be mediated in part by vascular endothelial growth factor (VEGF). It has been demonstrated 
in an in vivo model that VEGF can increase vascular permeability (Aiello et al. 1994) and that 
intraocular 
levels 
of 
VEGF 
in 
the 
eyes 
with 
RVO 
have 
been 
elevated 
(Campochiaro et al. 2009). 
Ranibizumab (Lucentis®) is a recombinant humanized Immunoglobulin G1 (IgG1) κ isotype 
monoclonal antibody fragment (Fab) that selectively binds VEGF-A. Ranibizumab 
(intravitreal injections of 0.5 mg) is approved for the treatment of ME due to RVO in more 
than 100 countries worldwide, including Japan. Based on the 6-month results of 2 phase III, 
randomized, double-masked, 12-month controlled studies – BRAVO study for BRVO and 
CRUISE study for CRVO (Brown et al. 2010, Campochiaro et al. 2010), ranibizumab (0.5 mg) 
was approved in June 2010 by the United States Food and Drug Administration, and in May 
2011 in the European Union for the treatment of ME secondary to RVO. Furthermore, based 
on the 3-month results of study RFB002E2301, a phase III, open-label, single arm, 
multicenter study for Japanese patients, ranibizumab (0.5 mg) was approved in Aug 2013 by 
the Ministry of Health, Labour and Welfare in Japan for the treatment of ME due to RVO. 
In BRAVO study, monthly treatment with both 0.3 mg and 0.5 mg ranibizumab induced rapid 
best-corrected visual acuity (BCVA) improvement within the first week followed by 
continued gradual improvement up to Month 6. The visual acuity (VA) gain was maintained 
on average until Month 12 by the pro re nata (PRN) treatment administered as from Month 6. 
The observed safety profile of ranibizumab was consistent with the previously established 
safety profile of ranibizumab in wet age-related macular degeneration (wAMD) patients and 
no new ranibizumab or intravitreal injection procedure related adverse events (AEs)/risks 
were identified in RVO patients (Campochiaro et al. 2010). In Japan, the phase III study 
(CRFB002E2301) confirmed these findings in Japanese patients (Kamei et al. 2016). 
Recently BRIGHTER study (phase IIIb study for BRVO using ranibizumab) has confirmed 
the efficacy and safety for 24 months using VA stability-guided PRN dosing for 0.5 mg 
ranibizumab (as approved in the EU SmPC) and each subgroup analyses (e.g. macular 
ischemia, duration of vision deterioration by BRVO and baseline VA) also confirmed that 

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clinically relevant increase in VA was observed irrespective of the differences of these factors 
(Tadayoni et al. 2016). In addition to these studies, VIBRANT study (aflibercept phase III 
study for BRVO) and MARVEL study (ranibizumab versus bevacizumab using PRN dosing) 
confirmed the efficacy and safety of anti-VEGF treatment for BRVO (Clark et al. 
2016, Narayanan R et al. 2015). 
Based on the result of these studies, anti-VEGF treatment is recommended as standard of care 
in patient with BRVO in overseas guidelines (Pulido et al. 2016, The ROYAL COLLEGE of 
OPHTHLMOLOGIST. 2015), and it has established as the standard treatment in patients with 
BRVO in Japan. 
However there are cases of repeated recurrences and poor responders to anti-VEGF therapy. 
In BRIGHTER study, more than 40% of patients needed more than twelve ranibizumab 
injections in ranibizumab monotherapy arm. In addition especially in Japan, due to high 
co-pay financial burden for patients (especially younger patients with RVO and diabetic 
macular edema (DME)), Japanese physicians and patients demand the way to reduce the 
number of anti-VEGF drug injections while maintaining efficacy. Hence it needs to be further 
examined how to deal with those patients that requires many anti-VEGF injections. 
Before anti-VEGF drugs were approved with ME secondary to BRVO, grid laser 
photocoagulation was the gold standard, and this exceled in maintaining VA (The Branch 
Vein Occlusion Study Group 1984). Therefore, medical experts expect the effect of laser 
photocoagulation to reduce the number of anti-VEGF injections when used in combination 
with anti-VEGF therapy. 
A few small scale single center past studies demonstrated that laser combination therapy 
potentially reduced the number of anti-VEGF drug injections in BRVO (Hayashi et al. 
2011, Donati et al. 2012, Farese et al. 2014, Salinas-Alaman et al. 2011, Iesato et al. 2016). 
Moreover, navigated laser photocoagulation (NAVILAS®) combined with ranibizumab 
contributed to reduce the number of ranibizumab injections in DME because of accuracy of 
the navigated laser system towards the pathologic area (e.g. leaking points and fluid area) 
(Liegl et al. 2014, Kozak et al. 2011, Neubauer et al. 2013). These results indicate that 
macular laser photocoagulation combined with anti-VEGF drug has a potential to reduce the 
number of anti-VEGF drug injections if it is used properly. 
In this study, we will apply a new laser photocoagulation method, which we call Grid&Direct 
short pulse laser photocoagulation. Basically, the method is based on a modified Early 
Treatment Diabetic Retinopathy Study (ETDRS) procedure in DME. Moreover, this study 
will adopt a short pulse laser method to reduce the risk for retinal tissue damage (e.g. 
expanding atrophic creep and retinal hemorrhage).
 
 
  
We expect the photocoagulation method used in this study will allow for a significant 
reduction of recurrences and therefore ranibizumab injections in BRVO patients. This study 
aims to show a superior benefit with regards to the reduction of ranibizumab injections in the 
laser photocoagulation combination arm without loss of efficacy and safety. 
We expect that this phase IV study will further help to reduce the treatment burden for 
Japanese BRVO patients and will contribute to the advancement of BRVO treatment in Japan. 

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1.2 
Purpose 
The present study will generate comparative efficacy and safety data as well as injection 
frequency data for 0.5 mg ranibizumab using a PRN dosing as defined in the protocol (i.e., 
according to the Japanese label of ranibizumab), administered with Grid&Direct short pulse 
laser photocoagulation versus 0.5 mg ranibizumab monotherapy using the same dosing (the 
current standard treatment) up to Month 12 in Japanese patients with visual impairment due to 
ME secondary to BRVO.
 
 
 The results of this study will provide 1 year 
safety, efficacy and injection frequency data to further guide recommendations on the use of 
ranibizumab with or without laser photocoagulation in BRVO. 
2 
Study objectives and endpoints 
2.1 
Primary objective 
To demonstrate that PRN regimen (PRN, according to the Japanese label of ranibizumab) 
with 0.5 mg ranibizumab combined with Grid&Direct short pulse laser photocoagulation 
reduces the burden of frequent ranibizumab injections as compared to ranibizumab 
monotherapy. The primary objective will be assessed by the difference in the mean number of 
ranibizumab injections applied up to Month 11 between the 2 treatment arms. 
2.2 
Secondary objectives 
The secondary objectives of this study are as follows: 
• To evaluate the efficacy of each arms as assessed by BCVA. 
• To evaluate the efficacy of each arms as assessed by center subfield thickness (CSFT). 
• To evaluate the safety of ranibizumab monotherapy and ranibizumab combined with 
Grid&Direct short pulse laser photocoagulation therapy in Japanese patients as assessed 
by the type, frequency, and severity of ocular and non-ocular AEs from Baseline (Day 1) 
to Month 12. 

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3 
Investigational plan 
3.1 
Study design 
This is a phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study. 
Patients will be randomized in a 1:1 ratio to 1 of the 2 treatment arms; i.e. Arm 1 ranibizumab 
monotherapy, Arm 2 ranibizumab with Grid&Direct short pulse laser photocoagulation 
combination therapy. 
In addition to screening and Baseline (Day 1), there will be monthly visits from Month 1 to 
Month 12. 
There will be 3 periods in this study: the Screening Period, Treatment Period and Follow-up 
Period (Figure 3-1). 

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Figure 3-1 
Study design 
 
 
Abbreviations: BSL= Baseline, EOT = End of Treatment Period, EOS = End of Study, S= Screening. 
Screening Period: Day -30 to Day -1 
Screening (Visit 1) to occur between Day -30 and Day -1 where screening assessments will be 
done between Day -30 and Day -4 after signing the informed consent form to check the 
eligibility for the study and administration of pre-ranibizumab treatment antimicrobials will 
occur  between Day -3 to Day -1. 
Treatment Period: Baseline (Day 1) to Month 11, PRN treatment with monthly 
monitoring 
After eligibility confirmation and randomization at Baseline (Day 1), patients will receive one 
of the below treatment.   
Arm 1 (ranibizumab monotherapy) 
Patients will start study treatment on Baseline (Day 1) and receive further ranibizumab 
treatment using PRN regimen i.e., according to the Japanese label of ranibizumab. 
Arm 2: (ranibizumab + Grid&Direct short pulse laser photocoagulation 
combination therapy) 
Patients will start study treatment on Baseline (Day 1) and receive further ranibizumab 
treatment using PRN regimen i.e., according to the Japanese label of ranibizumab. The laser 
treatment must be given to the target within vascular arcades as soon as indicated. 
The criteria for PRN of injections of ranibizumab are described in Section 5.5.4.2. Refer 
to Section 5.5.4 and Section 5.5.4.1 for more details on treatment administration. 
Treatment Period 
BSL (Day 1) 
Randomization 
Visit 2 
Screening  
Period 
Day  - 30 to  
Day  - 1  
Ranibizumab with laser photocoagulation 
  
Day 1 to Month 11 
Ranibizumab monotherapy 
  
M 11 
EOT Visit 13   
M 12 
 EOS Visit 14   
Follow-up 
Period 
S 
Day -30 to -1 
Visit 1 

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Post-treatment Follow-up Period: Month 11 to Month 12 
The last study assessment will be performed at Month 12, i.e., 1 month after the last possible 
ranibizumab injection/laser treatment in this study. 
3.2 
Rationale for study design 
A 2-arm design is required to compare ranibizumab administered with the laser treatment to 
ranibizumab monotherapy. To focus on collection of additional data for ranibizumab in a PRN 
dosing regimen as real world treatment using mainly 
 guided methods in Japan and given 
its known efficacy profile, a 1:1 randomization scheme is considered appropriate. 
An open-label study design has been chosen because masking of the laser treatment is not 
feasible. Laser burns are visible by fundus examination to the investigator and patients with a 
history of laser treatment would be able to differentiate between the past and present burns.  
However, masking the treatment to the Vision Examiner who will be assessing the key 
secondary endpoint parameters (BCVA) has been chosen to provide as much unbiased 
assessment as possible. Efficacy and safety of ranibizumab applied as per the Japanese 
treatment recommendations will be assessed in both arms. 
Ranibizumab treatment and laser photocoagulation have different modes of action that, on 
average, are both beneficial for VA in patients with BRVO. Laser treatment has a stabilizing 
effect with low average BCVA gain but infrequent treatments, while ranibizumab confers a 
relatively higher BCVA gain at the expense of frequent (every month) monitoring (and 
possibly, treatment). Thus, the combination of the 2 treatments may result in synergistic 
effects. For example, the lasting effect of the laser treatment may result in better maintenance 
of the VA gains obtained with ranibizumab treatment such that the need for retreatment with 
ranibizumab or even follow-up visits is reduced. Therefore we choose the primary endpoint as 
the number of ranibizumab injections. 
The possibility of a synergistic effect is explored by treating patients with ranibizumab and 
the Grid&Direct short pulse laser photocoagulation in Arm 2 and comparing the results with 
those obtained with ranibizumab monotherapy (Arm 1). 
Gold standard of care for the treatment of ME due to BRVO was grid laser photocoagulation 
before. However, several recent large clinical trials, e.g. BRAVO, BRIGHTER and 
VIVLANT, show the efficacy of significant visual gain and long term safety profile of anti-
VEGF treatment. Therefore, the current standard treatment for BRVO in Japan is anti-VEGF 
therapy, which will be used as active-control in Arm 1. 
The patient population will be described in more detail in the Section 4 below. 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
The evidence from 2 studies in BRVO patients (BRAVO and BRIGHTER), starting with 6 
and 3 consecutive monthly injections respectively, then PRN treatment or VA stabilization 
guided PRN injections demonstrated that the gains in VA seen with ranibizumab treatment 
have a rapid onset (as early as day 8 after the first treatment), with on average maintenance of 
the improvement in BCVA over a 12-month period. 

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In Japan, the 3-month phase III confirmatory study (CRFB002E2301) confirmed these 
findings in Japanese patients. 
In MARVEL study (Narayanan et al. 2015), as 1 + PRN treatment, the mean gains of BCVA 
were +18.1 letters in ranibizumab monotherapy and the mean number of ranibizumab 
injections were 3.2 at 6 months. Authors suggested that the result was consistently good like 
BRAVO study. 
Therefore, a treatment regimen according to the approved Japanese label, as assessed in this 
study (Arm 1), is likely to result in significant gains in BCVA comparable to those seen in 
these studies. The efficacy assessments conducted at Months 1, 2 and 3 are appropriate to 
assess the fast onset of treatment effect. By assessing monthly BCVA from Month 1 onwards, 
the magnitude and profile of efficacy achieved with the individualized treatment regimen can 
be evaluated though Month 12. 
3.4 
Rationale for choice of comparator 
Anti-VEGF monotherapy (in this study, ranibizumab) is the standard treatment of ME due to 
BRVO and is approved in Japan since 20-Aug-2013. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits  
The administration of ranibizumab in this study is according to the approved label in Japan in 
both treatment arms. The risks and benefits for treating Japanese patients with BRVO with 
ranibizumab have been assessed in the Japanese phase III “CRFB002E2301”study. Further 
safety assessments are currently conducted in the ongoing BRVO post marketing surveillance 
(PMS) study. The latest Pharmaceutical and Medical Devices Agency (PMDA) report from 
the BRVO PMS study has not shown any further safety concerns for ranibizumab in Japanese 
patients (5th Periodic safety report for patients with macular edema secondary to retinal vein 
occlusion. 2015).  
The main risks of laser photocoagulation are scotoma, visual field defect, atrophy, and retinal 
hemorrhage. In this study, we will adopt short pulse laser photocoagulation method that it will 
contribute to reduce these risks. 
The overall risks to subjects in this trial will further be minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring. 
The benefits for patients participating in this trial are the potential chance to obtain a similar 
efficacy to the standard treatment but with less numbers of injections, if randomized in the 
laser combination arm. 
Overall the results of this trial will provide evidence that help to further optimize the 
treatment strategies for Japanese BRVO patients. 

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4 
Population 
This study will include male and female patients (≥20 years old) who are diagnosed with 
visual impairment due to ME secondary to BRVO. Assuming an approximate 20% drop out 
rate, approximately 70 patients will need to be screened to have at least 56 patients found 
eligible and commencing treatment in the trial. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria (at 
Screening and confirmed at Baseline (Day 1) 
Inclusion criteria for patient 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male or female patients ≥20 years of age. 
Inclusion criteria for study eye 
3. Diagnosis of visual impairment exclusively due to ME secondary to BRVO. 
4. BCVA score at Screening and Baseline (Day 1) between 0.5 and 0.05 decimal (i.e., 
between 73 and 19 letters in ETDRS testing) with Landolt C charts inclusively (i.e., 
approximate logarithm of the minimum angle of resolution (logMAR) units of 0.3 to 1.30). 
5. At Baseline (Day1), a maximum BCVA gain of 0.2 units logMAR conversion inclusively 
from screening is allowed as long as the BCVA score does not exceed the upper limit of 
0.3 units logMAR. 
6. Increased central subfoveal thickness (> 300 µm at Baseline (Day 1) when measured by 
SD-OCT) 
7. Duration of vision deterioration ≤6 months (determined by self-report) at screening. 
If both eyes are eligible, the one with the worse VA at screening will be selected as study eye, 
unless, based on medical reasons, the investigator deems the other eye to be more appropriate 
for treatment and study.  
If the fellow eye presents with visual impairment due to ME secondary to RVO, it may also 
be treated with ranibizumab medication, laser photocoagulation or others and in line with the 
Japanese label and at the discretion of the investigator, however, any anti-VEGF treatments 
other than ranibizumab is not allowed. The fellow eye treated with ranibizumab is then 
labeled the fellow treated eye. Bilateral treatment with ranibizumab cannot be performed on 
the same day. Bilateral treatment indicates the number of patients who received 3 or more 
injections of ranibizumab (study and fellow treated eye) within a 30 ± 7 days period. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
Exclusion criteria for patient  
1. Inability to comply with study or follow-up procedures 
2. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing study treatment. Effective contraception methods include: 

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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
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 six weeks before taking study treatment.  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 m prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject. 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
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%), e.g., 
hormone vaginal ring or transdermal hormone contraception. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
In case of use of oral contraception women should have been stabile on the same pill for a 
minimum of 3 months before taking study treatment. 
Reliable contraception should be maintained throughout the study and for 3 months after 
study treatment discontinuation. 
Women are considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow-up hormone level assessment is she considered not of childbearing potential. 
3. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin laboratory test. 
Exclusion criteria for systemic medical history and conditions 
4. Any type of systemic disease or its treatment, including any medical condition (controlled 
or uncontrolled) that could be expected to progress, recur, or change to such an extent that 
it may bias the assessment of the clinical status of the patient to a significant degree or put 
the patient at special risk. 
5. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
6. Stroke or myocardial infarction less than 3 months before Screening. 
7. Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value 
of >100 mm Hg at Screening or Baseline (Day 1). Values will be measured 3 times using 
an automated validated device with an appropriately sized cuff. The repeat sitting 
measurements will be made at 1- to 2-minute intervals and the mean of the 3 
measurements will be used. Antihypertensive treatment can be initiated and must be taken 

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for at least 30 days after which the patient can be assessed for study eligibility a second 
time. 
8. Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation, 
or fluorescein. 
Exclusion criteria for ocular medical history and conditions 
Any ocular medical conditions that may confound interpretation of study results, compromise 
VA, affect ME or require medical or surgical intervention in the study eye during the 
12-month study period. These conditions include: 
For both eyes 
9. Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, 
keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline (Day 1). 
10. Uncontrolled glaucoma (intraocular pressure (IOP) ≥30 mm Hg on medication or 
according to investigator’s judgment) at the time of Screening or Baseline (Day 1) or 
diagnosed within 6 months before Baseline (Day 1). 
11. Inability of obtaining fundus photographs or fluorescein angiograms of sufficient quality 
to be analyzed. 
For study eye 
12. Cataract, aphakia, pseudoexfoliation, hemorrhage reducing VA, rhegmatogenous retinal 
detachment, macular hole, diabetic retinopathy and diabetic maculopathy requiring 
treatment, or choroidal neovascularization of any cause (e.g., age-related macular 
degeneration (AMD), ocular histoplasmosis, diabetic ME, pathologic myopia). 
13. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing VA 
by 3 lines or more (i.e. Cataract would be reducing acuity to 20/40 or worse if eye was 
otherwise normal). 
14. Brisk afferent pupillary defect. 
15. Neovascularization of the iris or neovascular glaucoma. 
16. Vitreomacular traction at the time of Screening or Baseline (Day 1). 
17. Structural damage within 0.5 disc diameter of the center of the macula (e.g., epiretinal 
membrane, scar, laser burn, foveal atrophy, dense pigmentary changes, dense subfoveal 
hard exudates). 
18. History of herpetic ocular infection or ocular toxoplasmosis. 
19. History of idiopathic central serous chorioretinopathy. 
Exclusion criteria for prior or current systemic medication 
20. Use of other investigational drugs within 30 days or 5 half-lives of Baseline (Day 1), 
whichever is longer. 
21. Use of any systemic anti-VEGF drugs within 6 months before Baseline (Day1) (e.g., 
sorafenib (Nexavar®), sunitinib (Sutent®), bevacizumab (Avastin®), ziv-aflibercept 
(ZALTRAP®)). 
22. Current or planned use of systemic medications known to be toxic to the lens, retina or 
optic nerve, including deferoxamine, chloroquine/hydroxychloroquine (Plaquenil®), 

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tamoxifen, phenothiazines other than temporary use with common cold and upper 
respiratory infection (i.e. exclude PL granules), and ethambutol. 
Exclusion criteria for prior or current ocular treatment 
For both eyes 
23. Treatment (or anticipated treatment in the fellow eye for non-RVO indications during the 
study) with any anti-angiogenic drugs (including any anti-VEGF agents) within 3 months 
before Baseline (Day1) in fellow eye or before Baseline (Day 1) in the study eye (e.g., 
pegaptanib (Macugen®), ranibizumab (Lucentis®), bevacizumab (Avastin®), and 
aflibercept (EYLEA®)). 
For study eye 
24. Panretinal laser photocoagulation within 1 month before Baseline (Day1) or anticipated or 
scheduled within the next 12 months (Study periods) following Baseline (Day1). 
25. Any giving of focal or grid laser photocoagulation before Baseline (Day1). 
26. Any intraocular procedure (including Yttrium-Aluminum-Garnet capsulotomy) within 2 
months before Baseline (Day1) or anticipated within the next 12 months following 
Baseline (Day1). 
27. Topical ocular or systemic corticosteroids administered for at least 30 consecutive days 
within 6 months before Screening. 
28. Use of intra- or periocular corticosteroids (including sub-Tenon) within 3 months before 
Screening. 
29. Any use of intraocular corticosteroid implants (e.g., dexamethasone (Ozurdex®), 
fluocinolone acetonide (Iluvien®)). 
30. History of optic neurotomy, sheathotomy, or filtration surgery at any time. 
31. Macular BRVO (Battaglia Parodi et al. 1999). 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
5 
Treatment 
5.1 
 Study treatment 
5.1.1 
Investigational and control drugs 
The investigational treatment used in this study is 0.5 mg ranibizumab applied PRN as 
intravitreal injection of 0.05 mL, with or without the laser treatment. Commercially available 
ranibizumab prefilled syringes (PFS) for injection will be supplied (open label) to each study 
center by Novartis Pharma K.K. for the treatment of study eye. Novartis Pharma K.K. will not 
be providing/supporting ranibizumab for the treatment of fellow eye however investigator can 
treat visual impairment of fellow eye due to ME secondary to RVO using ranibizumab 
purchased by patient. Each PFS contains ranibizumab in the concentration of 10 mg/mL. PFSs 
of ranibizumab are for single use only and the content of the PFS must not be split.  

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Arm 1: Patients with visual impairment due to ME secondary to BRVO are treated with 
ranibizumab monotherapy with an individualized stabilization-criteria-driven PRN dosing 
regimen as described in Section 5.5.4.1 and Section 5.5.4.2. 
Arm 2: Patients with visual impairment due to ME secondary to BRVO are treated with 
ranibizumab with an individualized stabilization-criteria-driven PRN dosing regimen. The 
laser photocoagulation is applied as described in Section 5.5.4.1 and Section 5.5.4.2. 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug and control drug are included in this trial. 
5.2 
Treatment arms 
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1. 
Arm 1: ranibizumab monotherapy 
Arm 2: ranibizumab with Grid&Direct short pulse laser photocoagulation combination 
therapy 
5.3 
Treatment assignment and randomization  
At Baseline (Day1) all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms.  
The randomization will be balanced by VA (0.3<, or ≥0.3 assessed by decimal VA which is 
translated into 58 letters in EDTRS). 
The randomization scheme for patients will be reviewed and approved by a member of the 
Biostatistics Quality Assurance (BQA) Group. 
5.4 
Treatment blinding 
This is an open-label study; therefore treatment blinding (masking) is not applicable. However, 
masking of the Vision Examiner, assessing parameters constituting the secondary endpoint 
(BCVA), will be chosen at each site before the study start. Therefore, the Vision Examiner 
will not be allowed to access unmasked medical records and to perform any other tasks 
involving direct patient care which may unmask him/her to the patient’s treatment. 
5.5 
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 

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5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the investigator. 
At each site, the first patient is assigned patient number 1, and subsequent patients are 
assigned consecutive numbers (e.g. the second patient is assigned patient number 2, the third 
patient is assigned patient number 3). The investigator or his/her staff will contact the IRT and 
provide the requested identifying information for the patient to register them into the IRT. For 
studies using electronic Case Report Forms (eCRFs), only the assigned patient number must 
be entered in the field labeled “Patient ID” on the electronic data capture (EDC) data entry 
screen (e.g. enter ‘1’, ‘2’, etc.). Once assigned to a patient, the patient number will not be 
reused. If the patient fails to be randomized for any reason, the IRT must be notified within 2 
days that the patient was not randomized. The reason for not being randomized will be entered 
on the Screening Log, and the Demography eCRF should also be completed. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied with investigational drug in packaging. 
Immediately before dispensing and administering the investigational drug, Investigator staff 
will write the drug name, strength, Packaging lot number and expiry date from the label onto 
the source document (and/or Drug Accountability Log) containing that patient’s unique 
patient number. Site may apply an additional label/sticker on the drug kit containing the 
following information for accountability purpose:  Study number, Study name.  
5.5.3 
Handling of study and additional treatment 
5.5.3.1 
Handling of study treatment 
Study treatment will be supplied by Novartis at the study site and must be received by a 
designated person, handled and stored safely and properly, and kept in a secured location to 
which only the investigator and designees have access. Upon receipt, all study treatment must 
be stored according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance.  
Medication labels will be in the local language and comply with the legal requirements of 
Japan. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, unused packaging and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.5.3.2 
Handling of additional treatment 
Not applicable. 

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5.5.4 
Instructions for prescribing and taking study treatment 
For the entire trial, regardless of randomization, the following rules apply: 
• Ranibizumab should be administered in the study eye on the day of the study visit. In any 
case, study treatment has to occur within the visit window as described in Section 6. 
• Treatments of the fellow eye with ranibizumab must not be performed on the same day as 
treatments with ranibizumab of the study eye. 
• When ranibizumab and laser photocoagulation are to be applied on the same day to the 
same eye, the laser treatment has to be applied at least 30 minutes before the ranibizumab 
injection. When ranibizumab and laser photocoagulation are not to be applied on the same 
day to the same eye, laser treatment can be deferred for up to 14 days relative to the 
ranibizumab treatment. 
• Initially, Grid&Direct short pulse laser photocoagulation may be performed in a staged 
manner as macular hemorrhage and severe edema (thicker than 400 µm as a guide) resolve, 
i.e. initial laser treatment can be split into 2 or more sessions.  
• On days when ranibizumab and/or laser treatment is to be administered, efficacy 
assessments and pre-injection safety measures (tonometry, slit lamp and fundus 
examinations) must be conducted before administration of ranibizumab and/or laser 
photocoagulation. 
If study visit assessments and a corresponding treatment occur on separate days, a repeat 
ophthalmoscopy should be performed as safety check-up before treatment of the eye. Results 
will be documented in the source documents but not in the eCRF. If any concern arises, 
treatment needs to be cancelled and a re-evaluation needs to take place. Efficacy assessments 
(BCVA, 
) already performed at the scheduled study visit should not be repeated on the 
day of treatment unless the patient indicates a sudden change in vision. 
Instructions on how to prepare ranibizumab PFSs for intravitreal injection and its 
administration under aseptic conditions are provided in the package insert of the provided PFS. 
Information on pre- and post-injection procedures including administration of antibiotic eye 
drops is provided in Appendix 2 and Appendix 3, respectively. Laser photocoagulation should 
be applied as approved for the indication and further outlined below. Instructions on post-laser 
treatment procedures are outlined in Appendix 4. Study treatment (ranibizumab, laser 
photocoagulation) prescribed and dispensed to the patient during the study must be recorded 
on the dosage administration record eCRF. 
5.5.4.1 
Treatment Period (Day 1 to Month 11) 
Arm 1: Ranibizumab monotherapy 
Patients will start study treatment with ranibizumab on Baseline (Day 1) and having reached 
stable status (i.e., satisfied stabilization criteria as per Section 5.5.4.2) ranibizumab treatment 
may be temporarily discontinued. Patients should be monitored monthly for VA and disease 
activity. Ranibizumab injections are given using PRN regimen i.e., according to the Japanese 
label of ranibizumab. The minimum gap required between 2 injections of ranibizumab will be 
30 ± 7 days. 

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If there is no improvement in VA 
 imaging over the course of the first 3 injections, 
continued treatment is not recommended and the patient may receive alternative treatment at 
the investigator’s discretion (for consequences refer to Section 5.6.2). 
Arm 2: Ranibizumab + Grid&Direct short pulse laser photocoagulation 
Patients will start study treatment with ranibizumab on Baseline (Day 1) and having reached 
stable status (i.e., satisfied stabilization criteria as per Section 5.5.4.2), ranibizumab treatment 
may be temporarily discontinued. Patients should be monitored monthly for VA and disease 
activity. Ranibizumab injections are given using PRN regimen i.e., according to the Japanese 
label of ranibizumab. The minimum gap required between 2 injections of ranibizumab will be 
30 ±7 days. 
Grid&Direct short pulse laser photocoagulation treatment must be applied to the target within 
vascular arcades as soon as indicated. If in the investigator’s opinion dense macular 
hemorrhage and/or severe retinal edema preclude laser treatment, laser photocoagulation 
should be postponed until resolution of the hemorrhage permits laser treatment. The criteria 
for PRN of Grid&Direct short pulse laser photocoagulation is defined in laser operation 
manual in detail. 
Following the complete application of the initial laser treatment, further laser treatment can be 
applied in the presence of ME due to BRVO at the investigator’s discretion at minimal 
intervals of 30 ±7 days.  
Laser photocoagulation will be optional if BCVA is greater than or equal to 0.8 in decimal 
VA which is equivalent to 0.12 units in logMAR (or 79 letters in ETDRS) or in the absence of 
ME. 
5.5.4.2 
PRN (re-treatment/stabilization) criteria 
The PRN criteria for ranibizumab treatment is as detailed below: 
After Baseline (Day 1) visit, if any one or more criteria from the below list is met, the patient 
should be considered for ranibizumab treatment (re-treatment criteria) 
1. Center subfield thickness ≥ 300 μm 
2. An increase of CSFT ≥ 20% compare to minimum value during the treatment period 
3. The loss of VA due to disease activity secondary to BRVO (disease activity includes 
macular edema (ME), intra-retinal cysts, sub-retinal fluid, macular hemorrhage etc.). 
This criteria is based on Investigator's judgement including the following scenarios: 
a. The VA is expected to improve if the existing disease activity is  removed, hence 
investigator decides to treat with ranibizumab 
b. The VA is expected to be decreasing because of the existing disease activity, 
hence investigator decides to treat with ranibizumab 
c. The VA has decreased as compared to the previous month because of the 
appearance of disease activity, hence investigator decides to treat with 
ranibizumab (This criterion is to restart ranibizumab after interruption) 
• If all the above criteria are not satisfied, then the patient should not be treated with 
ranibizumab (stabilization criteria), i.e.,  
1. Center subfield thickness < 300 μm 

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2. An increase of CSFT < 20% compare to minimum value during the treatment period 
3. VA is stable and the disease activity is in the state of not affecting VA (based on 
investigator’s judgement). 
5.5.4.3 
Treatment of the fellow eye 
Patients who develop visual impairment due to ME secondary to RVO in the fellow eye 
(non-study eye) during the study that, in the investigator’s opinion, qualifies for and requires 
treatment, may be treated at the investigator’s discretion according to the standard treatment, 
including administration of ranibizumab. Ranibizumab will be injected in accordance with the 
rule of usual care and should be applied as per Japanese label. 
Treatments of the fellow eye with ranibizumab should not be performed on the same day as 
treatments with ranibizumab of the study eye. Treatment of the fellow eye must be scheduled 
in a way not to disturb the schedule for visits and treatments of the study eye. Treatment will 
be captured on the eCRF. The fellow treated eye must be monitored according to routine 
practice and AE(s) and serious adverse events (SAEs) are captured on eCRFs. If fellow eye is 
treated with ranibizumab, examinations will be same as study eye. 
Treatment with other anti-VEGF medication (e.g., pegaptanib (Macugen®), bevacizumab 
(Avastin®), aflibercept (EYLEA®)) and intra- or periocular corticosteroids (including sub-
Tenon) are prohibited. 
Treatment with ranibizumab for non-RVO indications in the fellow eye will be permitted in 
the same rule with RVO in the fellow eye within the limits of Japanese package insert, but the 
other anti-VEGF medication is prohibited. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Dose adjustments, i.e., adjustments of the injection volume of ranibizumab dose solution, are 
not permitted. 
Adjustments of the PRN dosing regimen of ranibizumab that is described as part of the study 
treatment administration in Section 3.1 and Section 5.5.4 are not permitted. 
Ranibizumab treatment should be withheld and treatment should not be resumed earlier than 
the next scheduled treatment in the event of: 
• A decrease in BCVA of ≥0.6 units in logMAR compared with the last assessment of VA, 
• An IOP of ≥30 mm Hg, 
• A retinal break, 
• Performed or planned intraocular surgery within the previous or next 28 days. 
Laser photocoagulation should be withheld and treatment should not be resumed earlier than 
the next scheduled treatment in the event of: 
• A significant increase in macular ischemia as judged by the investigator, 
• Absence of macular edema, 
• Dense macular hemorrhage. 
These changes must be recorded on the Dosage Administration Record eCRF. 

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5.5.6 
Rescue medication 
Rescue medication will not be permitted in this study. 
5.5.7 
Concomitant medication 
The investigator should instruct the patient to notify the study site about any relevant prior 
medications (especially those related to ocular treatment) and any medications he or she takes 
preceding Baseline (Day 1) (once the informed consent is signed) until the conclusion of the 
study participation. Any relevant medications and significant non-drug therapies administered 
preceding Baseline (Day 1) before start of study treatment will be listed on Prior medication 
therapy page of eCRF and all medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient starts treatment must 
be listed on the concomitant medications/significant non-drug therapies eCRF.  
Protocol specific medications (e.g., dilating drops, fluorescein dyes) and pre- and post-
injection medications (e.g., topical anesthetics, topical antimicrobials) used by a patient 
during the study are not considered concomitant medications although these are listed in 
eCRF if used. 
5.5.8 
Prohibited medication 
The following treatments are not allowed in the study eye throughout the entire study: 
• Pan retinal and sector laser photocoagulation on the outside of vascular arcade or any 
other type of intervention for RVO (e.g. vitrectomy, optic neurotomy, sheathotomy, 
filtration surgery). 
• Any type of intraocular surgery including cataract surgery. 
• Intra-/peri-ocular corticosteroids (including sub-Tenon, but excluding topical formulations 
of any drug) and intra-ocular corticosteroid implants (e.g. dexamethasone (Ozurdex®), 
fluocinolone acetonide (Iluvien®)). 
The use of the following medications is not allowed in both eyes throughout the entire 
study: 
• Non-study anti-angiogenic drugs (including any anti-VEGF drugs) (e.g. pegaptanib 
(Macugen®), bevacizumab (Avastin®), and aflibercept (EYLEA®)). 
The following systemic medications are not allowed throughout the entire study: 
• Corticosteroids, 
• Anti-VEGF drugs (e.g. sorafenib (Nexavar®), sunitinib (Sutent®), bevacizumab (Avastin®) 
and ziv-aflibercept (ZALTRAP®)), 
• Medications known to be toxic to the lens, retina or optic nerve including deferoxamine, 
chloroquine/hydroxychloroquine (Plaquenil), tamoxifen, phenothiazines other than 
temporary use with common cold and upper respiratory infection (i.e., exclude PL 
granules), and ethambutol. 
Furthermore, any type of investigational drug or investigational intervention (e.g. isovolumic 
hemodilution, intravitreal tissue plasminogen activator (TPA)) is prohibited throughout the 
study. 
Prohibited treatments are summarized in Table 5-1. 

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Table 5-1 
Prohibited treatment 
Medication 
Action to be taken 
Other anti-VEGF drugs (ocular or systemic) 
Discontinue study treatment and study 
Pan-retinal laser photocoagulation – study eye 
Intra-/peri-ocular corticosteroids (including sub-
Tenon) – study eye 
Discontinue study treatment and study 
Discontinue study treatment and study 
Intra-ocular corticosteroid implants – study eye 
Systemic corticosteroids  
Intraocular surgery  – study eye 
Deferoxamine 
Chloroquine/hydroxychloroquine 
Tamoxifen 
Phenothiazines other than temporary use with a 
common cold and an upper respiratory infection 
Ethambutol 
Investigational drugs and interventions 
Discontinue study treatment and study 
Discontinue study treatment 
Discontinue study treatment and study 
Discontinue study treatment 
Discontinue study treatment 
Discontinue study treatment 
Discontinue study treatment 
 
Discontinue study treatment 
Discontinue study treatment 
5.5.9 
Emergency breaking of assigned treatment code 
Not applicable. 
5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment 
Patients who successfully complete the study through Month 12 will be considered to have 
completed the study. 
No extension to this study has been planned. 
5.6.2 
Discontinuation of study treatment 
Patients can discontinue treatment because of the appearance of a new health condition 
suspected to require appropriate care or require medications prohibited by the protocol 
(Section 5.5.8), unacceptable AEs, refusal to continue treatment, or at the investigator’s 
discretion based on his/her clinical judgment. 
Study treatment must be discontinued under the following circumstances: 
• Emergence of the following AEs: 
• Rhegmatogenous retinal detachment 
• Stage 3 or 4 macular hole 
• Stroke or transient ischemic attack (TIA) 
• Pregnancy 
• Use of prohibited treatment as per Table 5-1. 
• Any other protocol deviation that results in a significant risk to the patient’s safety. 
The reason for study treatment discontinuation will be recorded on the Treatment Period 
Completion eCRF. 

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Patients who permanently discontinue study treatment and start certain prohibited treatments 
(see Table 5-1) should be withdrawn from the study and undergo all assessments for the 
Visit 14 (End of study (EOS)) as described in Table 6-1. 
Patients who discontinue study treatment and do not start a prohibited medication 
per Table 5-1 should NOT be considered withdrawn from the study and continue their 
scheduled follow-up assessments until Visit 14 (EOS). A Study Treatment Period Completion 
eCRF should be completed, giving the date and primary reason for stopping study treatment. 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table below. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients. 
5.6.4 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed. 

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5.6.5 
Early study termination by the sponsor 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as described in Section 5.6.2 for a 
prematurely withdrawn patients. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or IECs of the 
early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and procedures to be performed by study visits. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. Assessments are indicated with an “X” when they need to be performed. 
A planned study visit schedule will be established at the time of Baseline (Day 1) for all 
patients. Study assessments will be performed at Screening, Baseline (Day1), and at monthly 
visits (defined as every 30 days calculated from Baseline (Day1)) from Month 1 through 
Month 12, ± 7 days to allow for flexibility in scheduling. Ranibizumab should be 
administered in the study eye on the day of the study visit. Only when ranibizumab and laser 
photocoagulation are not to be applied on the same day to the same eye, laser treatment can be 
deferred for up to 14 days relative to the ranibizumab treatment. In the other case, study 
treatment has to occur within the visit window as specified in Table 6-1. 
Should a deviation from the study visit schedule occur, all efforts should be made to return to 
the planned visit schedule. 

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Table 6-1 
Assessment schedule 
Period 
Screening 
Treatment Period 
FUP 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Month  
(relative to BSL) 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
EOT 
M12 
EOS p 
Day (relative to BSL) 
-30 to -1 a 
1 
BSL 
30 
60 
90 
120 
150 
180 
210 
240 
270 
300 
330 
360 
Visit window 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests b 
- hematology 
  (incl. coagulation 
panel) 
- clinical chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum pregnancy test c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test c 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Vital signs d, e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Decimal BCVA d, f 
X g 
X g 
X 
X 
X  
X  
X 
X g 
X 
X 
X 
X 
X 
X g 

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Period 
Screening 
Treatment Period 
FUP 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Month  
(relative to BSL) 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
EOT 
M12 
EOS p 
Day (relative to BSL) 
-30 to -1 a 
1 
BSL 
30 
60 
90 
120 
150 
180 
210 
240 
270 
300 
330 
360 
ETDRS BCVA d, f 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ophthalmic 
examination h 
X g 
X g 
X 
X 
X 
X 
X 
X g 
X 
X 
X 
X 
X 
X g 
Tonometry d, i 
X g 
X g 
X 
X 
X  
X 
X 
X g 
X 
X 
X 
X 
X 
X g 
Color fundus 
photography  
X g 
 X k 
X k 
X k 
X k 
X k 
X k 
X g 
X k 
X k 
X k 
X k 
X k 
X g 
Dispense antibiotic 
medication l 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ranibizumab injection 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Grid&Direct short pulse 
laser treatment m 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Post injection safety n 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Follow-up contact o 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Period 
Screening 
Treatment Period 
FUP 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Month  
(relative to BSL) 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
EOT 
M12 
EOS p 
Day (relative to BSL) 
-30 to -1 a 
1 
BSL 
30 
60 
90 
120 
150 
180 
210 
240 
270 
300 
330 
360 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BCVA = best-corrected visual acuity, BSL = Baseline, EOS = End of Study, EOT = End of Treatment Period, ETDRS = Early Treatment 
Diabetic Retinopathy Study, FUP = Follow-Up Period, IOP = intraocular pressure, M = month, 
 
, PRN = Pro re nata, VA = Visual acuity, VEGF = Vascular endothelial growth factor. 
(X) Indicates that ranibizumab injection or laser treatment should be given PRN as per protocol. If the fellow eye presents with visual impairment due to 
ME secondary to RVO, it may also be treated with ranibizumab medication, laser photocoagulation in line with the Japanese label and at the discretion of 
the investigator, however, any anti-VEGF treatments other than ranibizumab is not allowed. The fellow eye treated with ranibizumab is then labeled the 
fellow treated eye. Bilateral treatment with ranibizumab cannot be performed on the same day. 
a.  Screening (Visit 1) to occur between Day -30 and Day -1 where screening assessments will be done between Day -30 and Day -4 after signing the 
informed consent form to check the eligibility for the study and administration of pre-ranibizumab treatment antimicrobials will occur between Day -3 to 
Day -1.  
b. Hematology includes: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential count (neutrophils, bands, lymphocytes, 
eosinophils, monocytes, basophils and other cells), and platelet count. In addition, the coagulation panel (activated partial thromboplastin and 
prothrombin time), D-dimer, and thrombin-antithrombin complex: TAT will be assessed. Clinical chemistry includes: sodium, potassium, chloride, 
bicarbonate, creatinine, glucose, total protein, albumin, total bilirubin, direct bilirubin, uric acid, urea, phosphorus, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, total cholesterol, low-density lipoprotein cholesterol and calcium. In addition, Leptin, 
highly sensitive C-reactive protein and VEGF will be assessed. 
c. Serum pregnancy test will be performed on women of childbearing potential at Screening and EOS visits. Urine pregnancy tests will be optionally 
performed to confirm pregnancy status during the course of the study. 
d. BCVA, vital signs, tonometry: Perform pre-treatment with ranibizumab and/or laser photocoagulation and before dilation. 
e. Vital signs will be taken after the patient has been sitting for 5 minutes, with back supported and both feet placed on the floor. Systolic and diastolic 
blood pressure will be measured 3 times. The repeat sitting measurements will be made at 1- to 2-minute intervals and the mean of the 3 
measurements will be used. Vital signs will include sitting pulse. 
f. BCVA: The VA examiner must be masked to the treatment arm. The VA examiner is not allowed to access unmasked medical records and to perform 
any other tasks involving direct patient care which may unmask him/her to the patient’s treatment. 
g. Assessments will be performed in both eyes. 

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h. Ophthalmic examinations will include slit lamp examination, anterior chamber examination, and direct and indirect ophthalmoscopy of the macular 
and peripheral retina. Must be performed pre-treatment with ranibizumab and/or laser photocoagulation. 
i. 
Tonometry: In the study eye, tonometry is conducted at every study visit in all treatment arms to assess IOP, regardless of treatment administration 
afterwards. On visits when ranibizumab and/or laser treatment is administered, also post-injection tonometry should be performed between 15 and 
60 minutes after treatment in the study eye. In the fellow untreated eye, tonometry will be conducted at Screening, Baseline (Day 1), Month 6, and 
the EOS visit. 
 
 
 
k. These assessments are optional if the investigator requires the respective information to assess the need for retreatment. 
l. Before the study treatment with ranibizumab, ensure that patients have self-administered their antimicrobials 4 times daily for 3 days before each 
scheduled study treatment and instruct patients to self-administer their antimicrobials again 4 times daily for 3 days post-treatment with ranibizumab. 
m. In Arm 2, the first laser treatment must be given to the target within vascular arcades as soon as indicated, but can be deferred by a maximum of 14 
days relative to the ranibizumab injection.  
n. Post injection safety after ranibizumab and/or laser treatment, comprising: central artery perfusion, vision check, IOP. (Perform finger count, hand 
motion, and light perception (when indicated) within 15 minutes post-treatment for the study eye only). 
o. Follow-up Contact: Contact the patient by telephone for safety evaluations 2 (± 1) days following each study visit when study treatment (ranibizumab 
and/or laser photocoagulation) is administered. 
p. EOS: For patients, who complete, withdraw or are discontinued early (refer to Section 5.6.2) from the study, perform 30 days (+ 7 days) following the 
last study treatment or the last study visit. 
 

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6.1 
Information to be collected on screening failures 
Patients who are screened but determined not eligible for treatment are considered screening 
failures. The reason for this will be documented on the Screening Log. In addition, for all 
screening failures, the Screening Visit date, demography eCRF, Informed Consent eCRF, 
inclusion/exclusion, reason of screen failure on Screening Disposition, Demography and SAE 
data will be collected. 
Adverse events that are not SAEs will be followed by the investigator and collected only in 
the source data. For all patients who have signed informed consent and are entered into the 
next period of the study will have all AEs occurring after informed consent is signed recorded 
on the AE eCRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients as shown 
in Table 6-1 include: 
Demography: date of birth, gender, race, ethnicity 
Study eye selection 
RVO specific baseline characteristics including date of BRVO diagnosis. Other assessments 
performed at screening to determine eligibility are listed in Table 6-1. 
6.3 
Treatment exposure and compliance 
Information regarding drug administration will be collected on the “Drug administration 
record” (DAR) eCRFs. The reason for dosing of ranibizumab or the reason for change of 
dosing must be described on the DAR page of the eCRF. 
The reason for dosing of ranibizumab/laser photocoagulation or the reason for dose/no dose 
will be described on the DAR eCRF for the study eye. 
In addition, confirmation of disease activity as assessed by the investigator through decreasing 
VA due to ME secondary to BRVO and abnormalities detected by 
 
 CF will be captured for the study eye. 
6.4 
Efficacy 
Efficacy assessments will include both functional and anatomical evaluations. The methods of 
evaluation and the parameters to be assessed are described below. 
These assessments are performed according to the schedule in Table 6-1. 
On days when ranibizumab and/or laser treatment is administered, efficacy assessments must 
be conducted before administration of ranibizumab and/or laser photocoagulation. 

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If study visit assessments and a corresponding treatment occur on separate days, efficacy 
assessments (BCVA, 
) already performed at the scheduled study visit would not be 
repeated on the day of treatment unless the patient indicates a sudden change in vision. 
6.4.1 
Decimal Best-Corrected Visual Acuity 
BCVA will be assessed in a sitting position using Decimal VA testing charts at an initial 
testing distance of 5 meters at every visit. VA examiners will examine it according to their 
standards’ practice. For the study eye, the BCVA will be assessed at every visit, and at 
Screening, Baseline (Day 1), Month 6, and EOS in the fellow untreated eye as per Table 6-1. 
6.4.2 
ETDRS Best-Corrected Visual Acuity 
BCVA will be also assessed in a sitting position using ETDRS VA testing charts at an initial 
testing distance of 4 meters. 
If it is not possible to perform a subjective refraction or VA testing at 4 meters because VA is 
too poor for the patient to read at least 4 letters on the refraction/VA chart at this distance, the 
refraction/VA testing should be attempted at 1 meter. Further details on refraction technique 
and VA testing will be described in the VA testing manual provided by Novartis. For the 
study eye, the BCVA will be assessed at Baseline (Day1), Month 6, and EOS as 
per Table 6-1. 
6.4.4 
Color fundus photography 
 
The ocular fundus is assessed by Color Fundus photography (CF) 
 
For both eyes, CF
 images will be taken at Screening, at Month 6, and at study completion 
(EOS) as per Table 6-1. 
 
 
Investigators will evaluate the images according to their standards’ practice. 

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Additional 
 CF images may 
be taken at other monthly visits at the investigator’s discretion. The investigator will evaluate 
the images according to their standards’ practices, will capture the presence or absence of 
macular edema, capillary leakage and non-perfusion within the 3 mm perifoveal subfield in 
the eCRF and may use the images to inform his or her decision for retreatment. The decision 
for retreatment needs based on his or her evaluation of the 
/CF images will be documented 
in the eCRF. 
6.4.8 
Appropriateness of efficacy assessments  
The efficacy assessments selected for this study are standard for this indication and patient 
population. 
6.5 
Safety  
Safety will be assessed by the type, frequency and severity of AEs. Methods applied for the 
evaluation of safety include ophthalmic examinations, vital signs and laboratory tests. Safety 
assessments are performed according to the schedule in Table 6-1. 
Post injection safety after ranibizumab and/or laser treatment, will be evaluated as mentioned 
in Table 6-1. Post-injection safety comprising the following: central artery perfusion, vision 
check, IOP. (Perform finger count, hand motion, and light perception (when indicated) within 
15 minutes post-treatment for the study eye only). 

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All ocular assessments enabling identification of possible AEs will be performed on both eyes. 
6.5.1 
Ophthalmic examinations 
The standard ophthalmic examinations include slit lamp examination, anterior chamber 
examination, direct and indirect ophthalmoscopy of the macular and peripheral retina, and 
tonometry. 
Slit lamp and fundus examinations will be performed prior to treatment with ranibizumab for 
study eyes at all visits and at Screening, Baseline (day1), Month 6, and EOS in the fellow 
untreated eye as per Table 6-1. Results will be assessed whether they are normal, clinically 
insignificantly abnormal or clinically significantly abnormal and will be recorded as such in 
the eCRF. Any clinically significant abnormalities of either eye will be recorded either in the 
Medical/ocular history eCRF or in the AE eCRF depending on when the test abnormality 
occurred (see Section 6.1). 
For both eyes, tonometry should be conducted at Screening, at Baseline (Day1), at Month 6 
and at EOS visit as per Table 6-1. Intraocular pressure in the study eye will be assessed 
before, as well as between 15 and 60 minutes after treatment with ranibizumab at every visit. 
The IOP values recorded in mmHg will be entered into the eCRF. 
6.5.2 
Vital signs 
These include assessment of the sitting blood pressure (systolic, diastolic measurement in 
mmHg) and pulse rate (in bpm) at each visit. 
On days when ranibizumab treatment is administered, vital signs will be measured prior to 
administration of ranibizumab. 
The results will be recorded in the eCRF. 
Clinically notable vital signs are defined in Appendix 1. 
6.5.3 
Height and weight  
Height (in cm) and weight (in kg, in indoor clothing but without shoes) will be assessed at 
screening (Visit 1) only. The results will be recorded in the eCRF. 
6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. 
Whether a sample was collected at Screening and EOS or not will be recorded in the eCRF. 
Laboratory results will not be recorded in the eCRF but transferred directly from the central 
laboratory to data management upon completion of the study. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential count 
(neutrophils, bands, lymphocytes, eosinophils, monocytes, basophils and other cells), and 

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platelet count will be measured. In addition, the coagulation panel (activated partial 
thromboplastin and prothrombin time), D-dimer, and thrombin-antithrombin complex: TAT 
will be assessed. 
6.5.4.2 
Clinical chemistry 
Sodium, potassium, chloride, bicarbonate, creatinine, glucose, total protein, albumin, total 
bilirubin, direct bilirubin, uric acid, urea, phosphorus, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, total cholesterol, low-density 
lipoprotein cholesterol and calcium will be measured. In addition, Leptin, highly sensitive 
C-reactive protein and VEGF will be assessed. 
6.5.4.3 
Urinalysis 
Not applicable. 
6.5.5 
Electrocardiogram (ECG) 
Not applicable. 
6.5.6 
Pregnancy assessments 
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
screening (Visit 1) and study completion visits (Visit 14). Additional pregnancy testing might 
be performed if needed. 
Serum pregnancy test will be performed on women of childbearing potential at Screening and 
EOS visits. Urine pregnancy tests will be optionally performed as per Table 6-1 to confirm 
pregnancy status during the course of the study. 
Patients who are determined to be post-menopausal as defined in Section 4.2 before or during 
the study are not required to undergo subsequent pregnancy testing. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected for this study are standard for this indication and patient 
population. 
6.6 
Other assessments 
No additional tests will be performed in this study. 
6.6.1 
Clinical Outcome Assessments (COAs) 
Not applicable. 
6.6.2 
Resource utilization 
Not applicable. 
6.6.3 
Pharmacokinetics 
Not applicable. 

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6.6.4 
DNA sampling 
Not applicable. 
6.6.5 
Pharmacogenetics 
Not applicable. 
6.6.6 
Other biomarkers 
Not applicable. 
7 
Safety monitoring 
7.1 
Adverse events 
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study 
until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
AE irrespective if a clinical event has occurred. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. Adverse events will be collected from signing of ICF through 
the end of trial. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline (Day1) or the previous visit, or values which are considered to be non-typical in 
patient with underlying disease. Investigators have the responsibility for managing the safety 
of individual patient and identifying AEs. 
Adverse events must be recorded in the AEs eCRF under the signs, symptoms or diagnosis 
associated with them, accompanied by the following information: 
1. the severity grade. If CTCAE grading does not exist for an AE, use 1=mild, 2=moderate, 
3=severe, 4=life threatening. CTCAE Grade 5 (death) is not used, but is collected in other 
eCRFs (Study Completion). 
2. site (non-ocular, left eye, right eye, both eyes). 

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3. its relationship to the ocular injection/study drug(s) (Yes/No). 
4. its duration (start and end dates or if continuing at final exam). 
5. whether it constitutes an SAE (see Section 7.2.1 for definition of SAE). 
All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e. further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this AE; concomitant medication 
given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The 
action taken to treat the AE should be recorded on the Adverse Event eCRF. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the package insert. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed. Any new information 
regarding the safety profile of the medicinal product that is identified between package insert 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.2. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Paper SAE form will be used in this study. Information about all SAEs is collected and 
recorded on the Serious Adverse Event Report Form. The investigator must assess the 
relationship of any SAE to study drug, complete the SAE Report Form in Japanese and send 
the completed, signed form by fax within 24 hours to the local Novartis Drug Safety and 
Epidemiology Department (DS&E). The telephone and telecopy number of the contact 
persons in the local department of Clinical Safety and Epidemiology, specific to the site, are 
listed in the investigator folder provided to each site. The original copy of the SAE Report 

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Form and the fax confirmation sheet must be kept with the eCRF documentation at the study 
site.  
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not (where applicable), and whether the patient continued or withdrew from study 
participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a DS&E Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
Not applicable. 
7.4 
Renal safety monitoring 
Not applicable. 
7.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer. 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR eCRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE. Guidance for capturing 
study treatment errors including misuse/abuse is given in Table 7-1. 

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Table 7-1  
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error 
type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes,  
Yes, even if not associated 
with a SAE 
 
7.6 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. If any birth defects/congenital anomaly noted, it 
should be reported as SAE separately. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis DS&E Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the 
Novartis study drug of any pregnancy outcome. Any SAE experienced during pregnancy must 
be reported on the SAE Report Form. 
7.7 
Prospective suicidality assessment 
Not applicable. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on eCRFs must be traceable to these source documents in the patient's file. The investigator 

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must also keep the original informed consent form signed by the patient (a signed copy is 
given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
8.2 
Data collection 
Field monitors will review the eCRFs for completeness and accuracy and instruct site 
personnel to make any required corrections or additions. The designated investigator staff will 
enter the data required by the protocol into the eCRF. The eCRFs have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, 
Investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs and, allow 
modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
8.3 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization; CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staffs are required to respond promptly to queries and to make any necessary 
changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
the Novartis/designated CRO. The Novartis/CRO data management staff will perform a 
reconciliation of the data entered into the eCRF versus what is received from the central 
laboratory. At a minimum, this reconciliation will include header reconciliation, visit window 
checks, duplicate record checks, out of range checks as defined by the Clinical Trial Team and 
checks to address missing laboratory data. 
Randomization codes and data about all study treatments dispensed to the patient will be 
tracked in the drug dispensing log eCRF. The occurrence of any protocol violations will be 
determined. After these actions have been completed and the data has been verified to be 

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complete and accurate, the database will be declared locked and made available for data 
analysis. 
Authorization is required prior to making any database changes to locked data, by the Medical 
Advisor or Equivalent; prior authorizing the database un-lock, a CTT meeting will be hosted, 
to discuss the issues leading to database unlock and update. For EDC studies, after database 
lock, the investigator will receive paper copies of the patient data for archiving at the 
investigational site. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis 
The statistical analysis will be performed by Product Lifecycle Services (PLS) of Novartis. 
The primary objective is to demonstrate that PRN regimen of 0.5 mg ranibizumab with 
Grid&Direct short pulse laser photocoagulation reduces the burden of frequent ranibizumab 
injections as compared to ranibizumab monotherapy. 
The primary objective will be assessed by the mean number of ranibizumab injections applied 
up to Month 11. 
Summary statistics for continuous variables will generally include the number of patients (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of patients in each category will be presented. 
P-values presented will be 2-sided unless otherwise specified. 
Data analyses will be presented at all time points assessed, by treatment group including 
graphical presentations, where appropriate. For statistical analysis purpose, baseline values 
will be considered to be the last available values collected before Day 1. Day 1 will be defined 
for statistical analysis purpose as the time point of first treatment (associated to baseline visit).  
For patients who receive a prohibited medication for the study indication in the study eye, the 
efficacy data will be excluded from the per-protocol efficacy analysis. 
Further details will be provided in the statistical analysis plan (SAP). 
9.1 
Analysis sets 
The Randomized Set will consist of all randomized patients. 
The Full Analysis Set (FAS) will consist of all randomized patients who received at least one 
administration of ranibizumab injection. In case there are safety concerns after administration 
of laser photocoagulation at Baseline (Day 1) and ranibizumab injection is not given during 
the entire study, the patient will still be included in the FAS, as there was an intention to treat 

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the patient with ranibizumab. Following the intent-to-treat principle, patients will be evaluated 
according to the treatment assigned to at randomization. 
No data will be excluded from the FAS analyses because of protocol deviations. 
The Per Protocol Set (PPS) will consist of all patients in the FAS who received at-least the 
first mandatory administration of ranibizumab injection and have at least one post-baseline 
assessment for BCVA and have no clinically significant protocol deviations. 
Clinically significant protocol deviations will be defined in the Statistical Analysis Plan. The 
criteria and determination of clinically relevant protocol deviations and patient specific 
identification of data to be excluded from the PPS will be databased and finalized prior to 
database lock. 
The Safety Set will consist of all patients who received at least one administration of 
ranibizumab injection and had at least one post-baseline safety assessment. The statement that 
a patient had no AEs also constitutes a safety assessment. Patients will be evaluated according 
to treatment received. 
9.2 
Patient demographics and other baseline characteristics 
9.2.1 
Demographics and baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables (including the baseline values of the secondary efficacy variables) for each treatment 
group and for all patients in the randomized set. The number and percentage of patients in 
each category will be presented for categorical variables for each treatment group and all 
patients. 
Demographic and baseline disease characteristics will be summarized for the variables listed 
in Section 6.2. 
9.2.2 
Medical history 
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
tabulated by site (non-ocular, ocular (study/fellow eye)), system organ class (SOC) and 
preferred term of the MedDRA dictionary. Other relevant baseline information will be listed 
and summarized as appropriate with descriptive statistics. Analyses will be based on the 
Randomized Set. 
9.3 
Treatments 
9.3.1 
Study treatment 
Descriptive statistics will be provided to characterize study treatment using the Safety Set. 
The number of patients receiving ranibizumab injections and laser treatments will be 
presented in frequency tables and cumulatively by treatment group. Summaries will be 
presented for the study eye only and for all ranibizumab injections/laser treatments in both the 
study eye and the fellow treated eye as appropriate. Other data related to the treatment or 
application procedure will be summarized as appropriate. 

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9.3.2 
Bilateral treatment 
The number of patients who received 3 or more injections of ranibizumab (study and fellow 
treated eye) within a 30 ± 7 days period will also be summarized by treatment group within 
the Safety Set. 
9.3.3 
Prior and concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized 
study treatment and the date of the last study visit will be a concomitant medication, including 
those which were started pre-baseline and continued into the period where study treatment is 
administered. 
Tables will show the overall number and percentage of patients receiving at least one 
treatment of a particular ATC code and at least one treatment in a particular anatomical main 
group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term using the Safety Set. 
9.4 
Analysis of the primary variable 
9.4.1 
Variable 
The primary variable is the mean number of ranibizumab injections applied up to Month 11 
between the 2 treatment arms in patients with visual impairment due to ME secondary to 
BRVO. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be conducted at Month 12 within the FAS using observed data. 
The following 1-sided hypothesis will be tested at the alpha level of 0.025: 
H0: µRanibizumab−Laser −µRanibizumab−Mono = 0 versus 
H1: µRanibizumab−Laser −µRanibizumab−Mono ≤ 0 
where µRanibizumab−Laser and µRanibizumab−Mono are the unknown mean values of the number 
of ranibizumab injections for the related treatment arms up to Month 11. 
The statistical hypothesis testing of the number of ranibizumab treatments will be based on a 
stratified Cochran-Mantel-Haenszel (CMH) test. Stratification will be done based on 
categories of baseline decimal VA (<0.3, or ≥ 0.3). Difference of mean number of injections, 
95% confidence interval (CI) of difference and one-sided p-value of the CMH test will be 
reported. 

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9.4.3 
Handling of missing values/censoring/discontinuations 
No imputation is required for the primary endpoint which is number of ranibizumab injections, 
based on PRN regimen that is the number of injections during the study period will be used 
for the primary endpoint. 
9.4.4 
Sensitivity analyses 
For sensitivity purposes, the primary analysis will be repeated for the PPS population. Any 
major discrepancies in the results across analyses will be investigated as necessary. 
The primary analysis may also be supported by using a stratified non-parametric Wilcoxon-
Mann-Whitney test. Further analyses performed if any, will be provided in SAP. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
The following secondary efficacy endpoints will be evaluated for the study eye: 
• The mean change in BCVA from Month 1 through Month 12 compared to Baseline 
(Day1) using decimal chart converted to be logMAR units, and ETDRS (Month 6, and 
Month 12) by both the treatment arms. 
• The mean average change in BCVA from Month 1 through Month 12 compared to 
Baseline (Day1) using decimal chart converted to be logMAR units by both the treatment 
arms. 
• The proportion of patients achieving BCVA improvement of ≥5, ≥10, ≥15, and ≥30 letters 
and proportion of patients experiencing a loss of <15 letters from Baseline (Day1) to 
Month 12 by treatment arms. 
• The proportion of patients reaching BCVA values ≥73, ≥80, and ≥85 letters (approximate 
0.5, 0.8, and 1.0 Decimal equivalent) at Month 12 by treatment arms. 
• The mean change in CSFT from Month 1 through Month12 compared to Baseline (Day1) 
by the treatment arms. 
• The mean average change in CSFT from Month 1 through Month12 compared to Baseline 
(Day1) by the treatment arms. 
The analyses for the secondary endpoints are described below. 
All endpoints relating to secondary objectives will also be summarized descriptively. 
Summary statistics will include relative and absolute frequencies for the categorical variables 
and the number of patients (N), minimum, mean, median and maximum for continuous 
variables. Further analyses, if required, will be described in SAP. 
9.5.1.1 
BCVA from Month 1 through Month 12 
The mean change in BCVA from Month 1 through Month 12 will be compared to Baseline 
(Day1) using decimal chart and ETDRS (only at Baseline (Day1), Month 6, and Month 12) 
between the 2 treatment arms. The analyses at each visit will be based on an analysis of 
variance (ANOVA) model with treatment group, and stratification factors. Stratification will 
be done based on categories of baseline decimal VA (<0.3, or ≥ 0.3). The Least Squares 

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Means (LS Means) estimates of BCVA compared to Baseline (Day1), difference of LS Means, 
their 95% confidence interval (CI) and the p-value (related to the null hypothesis that 
difference in mean change is zero) will be reported. 
The mean average change in BCVA from Month 1 through Month 12 will also be compared 
to baseline characteristic to the above model using decimal chart converted to be logMAR 
units by both the treatment arms. 
To obtain the mean average BCVA change from Month 1 through Month 12, the sum of 
single patient’s average BCVA changes will be divided by the number of patients.  
The average change in BCVA will be calculated for each single patient as follows: 
 
Average Δ BCVA = 
Δ BCVA𝑀𝑀1 + Δ BCVA𝑀𝑀2 + ….+ Δ BCVA𝑀𝑀12
12
 
Where Δ BCVAMx = change in BCVA from Baseline (Day1) at Month x 
The analyses will be conducted within the FAS using the LOCF approach. 
Endpoints related to the number and proportion of patients with BCVA letter gain or loss 
from Baseline (Day1) will be analyzed via stratified CMH test with stratification factors as 
described above. 
9.5.1.2 
Central subfield thickness from Month 1 through Month 12 
The mean change in investigator-assessed CSFT from Month 1 through Month 12 will be 
compared to Baseline (Day1) by the treatment arms. The analyses at each visit will be based 
on an analysis of variance (ANOVA) model as analogous to BCVA. 
The mean average change in investigator-assessed CSFT from Month 1 through Month 12 
will also be compared to Baseline (Day1) analogous to the above model by both the treatment 
arms. 
The analyses will be conducted within the FAS using the LOCF approach. 
9.5.1.3 
Handling of missing values/censoring/discontinuations 
For the secondary efficacy variables (BCVA, CSFT etc.), the analysis will follow a LOCF 
approach with the specification that missing values will be replaced by the last post baseline 
observation before the missing time point. 
9.5.1.4 
Sensitivity analyses 
For sensitivity purposes, the secondary efficacy analysis may be repeated for the PPS 
population using as observed and LOCF approach. Any major discrepancies in the results 
across analyses will be investigated as necessary. 
9.5.2 
Safety variables 
Safety parameters will be AEs, ophthalmic examinations, IOP, vital signs, and laboratory 
results. 

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9.5.2.1 
Adverse events 
Adverse events will be deemed treatment emergent if the onset date is on or after the date of 
first study treatment (Day 1). All treatment-emergent AEs will be summarized. Any AEs 
recorded prior to the start of study treatment will be listed separately and together with all 
other AEs. 
Adverse events will be presented separately by site (non-ocular, study eye, fellow eye). 
Adverse events will be summarized by treatment group, presenting the number and 
percentage of patients having an AE in each primary system organ class and having each 
individual AE based on the preferred term. Patients who experienced multiple AEs for a 
preferred term will be counted once, similarly for patients with multiple AEs per system organ 
class. 
All information pertaining to AEs noted during the study will be listed by patient, detailing 
AE (e.g., verbatim given by the investigator as well as the system organ class and preferred 
term according to MedDRA), date of starting and ending, causality, severity, relationship to 
the study drug or procedure, and eye (for ocular events). The AE onset will also be shown 
relative (in number of days) to the day of (first) initial study treatment (ranibizumab injection 
or laser photocoagulation as applicable) and relative (in number of days) to the Day 1. 
Summary tables will also be presented and described for subsets of AEs, e.g. events 
potentially related to VEGF-inhibition. Adverse events which are part of the Risk 
Management plan (RMP) will be listed based on the latest RMP version available at the time 
of DBL. 
The following AE listings will be provided: 
• Any AE recorded before Day 1. 
• Any treatment-emergent AEs with the exception of ocular AEs of the fellow untreated eye 
starting on or after first treatment with ranibizumab within this eye. 
• Any treatment-emergent AEs of the fellow treated eye starting on or after the first 
treatment with ranibizumab within this eye. 
• Any AEs for patients who (bilateral patients) received 3 or more injections of study drug 
within a 30 ± 7 days period starting on or after the third injection within the 30 ± 7 days 
period. 
Deaths, SAEs, and AEs leading to discontinuation of study treatment will be listed separately 
and, if appropriate, summarized by primary system organ class and preferred term. 
9.5.2.2 
Laboratory data 
Laboratory data for two groups of tests (hematology and chemical chemistry) will be 
summarized by presenting shift tables using extended normal ranges with thresholds 
representing clinical relevant abnormality and by presenting descriptive statistics of raw data 
and change from Baseline (Day1). Values outside the extended normal range will be listed by 
patient and treatment arm and flagged in data listings. 

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9.5.2.3 
Vital signs 
Vital signs will be summarized by presenting shift tables using thresholds representing 
clinical relevant abnormality (Appendix 1) and by presenting descriptive statistics of raw data 
and change from Baseline (Day1). Values outside the extended normal range will be listed by 
patient and treatment arm and flagged in data listings. 
9.5.2.4 
Ocular assessments 
Ocular assessments (including IOP) will be summarized descriptively by time point and 
treatment group based on the safety set. Intraocular pressure changes (pre-injection) from 
Baseline (Day1) by visit and changes from before dosing to after dosing within a visit will be 
descriptively summarized. 
Summaries will be presented separately for the study eye only and for the fellow treated eye. 
9.5.3 
Resource utilization 
Not applicable. 
9.5.4 
Pharmacokinetics 
Not applicable. 
9.5.5 
DNA 
Not applicable. 
9.5.6 
Biomarkers 
Not applicable. 
9.5.7 
PK/PD 
Not applicable. 

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9.7 
Interim analyses 
Not applicable. 
9.8 
Sample size calculation 
In order to detect a clinically meaningful difference in the number of injections (at least 2 
injections) at Month 11, as suggested by the principal investigators, this study will randomize 
at least 56 patients (28 per arm). 
For the sample size calculation, we will assume a difference between arms of 2 injections and 
a standard deviation (SD) of 2.32 (based on CAVNAV study (Liegl et al. 2014)). Based on 
the non-parametric Wilcoxon-Mann Whitney test for the difference in means this would 
require 25 patients per arm with 80% power and a 0.025 significance level (1sided), however 
assuming approximate 10% drops out rate, a total of at least 56 patients (28 per arm) are 
required to be randomized. 
Approximately 70 patients will need to be screened in order to have at least 56 patients 
eligible and commencing treatment in the trial. 
All sample size calculations performed using EAST 6.0. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 

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Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent or if applicable, after 
such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s legally acceptable representative (LAR) gives consent, the patient 
should be informed about the study to the extent possible given his/her understanding. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 

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10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 
12 
References 
References are available upon request. 
Aiello LP, Avery RL, Arrigg PG, et al (1994) Vascular endothelial growth factor in ocular 
fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med; 
331(22):1480-7. 

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Arakawa S, Arakawa S, Yasuda M, Nagata M, et al (2011) Nine-year incidence and risk 
factors for retinal vein occlusion in a general Japanese population: the Hisayama Study. Invest 
Ophthalmol Vis Sci;52(8):5905-9. 
Battaglia Parodi M, Saviano S, Ravalico G, (1999) Grid laser treatment in macular branch 
retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol; 237(12):1024-7. 
Brown DM, Campochiaro PA, Singh RP, et al (2010) Ranibizumab for macular edema 
following central retinal vein occlusion: six-month primary end point results of a phase III 
study. Ophthalmology; 117(6):1124-33. 
Campochiaro PA, Choy DF, Do DV, et al (2009) Monitoring ocular drug therapy by analysis 
of aqueous samples. Ophthalmology; 116(11):2158-64. 
Campochiaro PA, Heier JS, Feiner L, et al (2010) Ranibizumab for macular edema following 
branch retinal vein occlusion: six-month primary end point results of a phase III study. 
Opthalmology; 117(6):1102-12. 
Clark WL, Boyer DS, Heier JS, et al (2016) Intravitreal Aflibercept for Macular Edema 
Following Branch Retinal Vein Occlusion: 52-Week Results of the VIBRANT Study. 
Ophthalmology;123(2):330-6. 
Donati S, Barosi P, Bianchi M, et al (2012) Combined intravitreal bevacizumab and grid laser 
photocoagulation for macular edema secondary to branch retinal vein occlusion. Eur J 
Ophthalmol.; 22: 607–14. 
Farese E, Cennamo G, Velotti N, et al (2014) Intravitreal bevacizumab combined with grid 
photocoagulation in recurrent macular edema secondary to retinal vein occlusion. Eur J 
Ophthalmol.; 24: 761–70. 
Finkelstein D (1986) Argon laser photocoagulation for macular edema in branch vein 
occlusion. Ophthalmology; 93(7):975-7. 
Hayashi A, Yunoki T, Miyakoshi A, et al (2011) Intravitreal injection of bevacizumab 
combined with macular grid laser photocoagulation for macular edema in branch retinal vein 
occlusion. Jpn J Ophthalmol; 55: 625–31. 
Iesato Y, Imai A, Murata T, et al (2016 ) Effect of leaking capillaries and microaneurysms in 
the perifoveal capillary network on resolution of macular edema by anti-vascular endothelial 
growth factor treatment. Jpn J Ophthalmol ; 60(2):86-94. 
Ishibashi T, Li X, Koh A, et al (2015) The REVEAL Study: Ranibizumab Monotherapy or 
Combined with Laser versus Laser Monotherapy in Asian Patients with Diabetic Macular 
Edema. Ophthalmology;122(7):1402-15. 
Kamei M, Terasaki H, Yoshimura N, et al (2016) Short-term efficacy and safety of 
ranibizumab for macular oedema secondary to retinal vein occlusion in Japanese patients. 
Acta Ophthalmologica; in press. 
Kozak I, Oster SF, Cortes MA, et al (2011) Clinical evaluation and treatment accuracy in 
diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology; 
118(6):1119-24. 

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Liegl R, Langer J, Seidensticker F, et al ( 2014) Comparative evaluation of combined 
navigated laser photocoagulation and intravitreal ranibizumab in the treatment of diabetic 
macular edema. PLoS One;9(12):e113981. 
Mitchell P, Bandello F, Schmidt-Erfurth U, et al (2011) The RESTORE study: ranibizumab 
monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. 
Ophthalmology; 118(4):615-25. 
Narayanan R, Panchal B, Das T, et al (2015) A randomised, double-masked, controlled study 
of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of 
macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J 
Ophthalmol; 99(7):954-9. 
Neubauer AS, Langer J, Liegl R, et al (2013) Navigated macular laser decreases retreatment 
rate for diabetic macular edema: a comparison with conventional macular laser. Clin 
Ophthalmol; 7: 121-8. 
Operational manual for Grid&Direct short pulse laser photocoagulation, 04 Aug 2016. 
Pulido JS, Flaxel CJ, Adelman RA, et al (2016) Retinal Vein Occlusions Preferred Practice 
Pattern(®) Guidelines. Ophthalmology; 123(1):182-208. 
Salinas-Alaman A, Zarranz-Ventura J, Caire González-Jauregui JM, et al (2011) Intravitreal 
bevacizumab associated with grid laser photocoagulation in macular edema secondary to 
branch retinal vein occlusion. Eur J Ophthalmol; 21: 434–9. 
Tadayoni R, Waldstein SM, Boscia F, et al (2016) Individualized Stabilization Criteria-Driven 
Ranibizumab versus Laser in Branch Retinal Vein Occlusion: Six-Month Results of 
BRIGHTER. Ophthalmol; 123: 1332-44. 
The Branch Vein Occlusion Study Group (1984) Argon laser photocoagulation for macular 
edema in branch vein occlusion, The Branch Vein Occlusion Study Group. Am J 
Ophthalmol;98(3):271-82. 
The ROYAL COLLEGE of OPHTHALMOLOGISTS (2015) Retinal Vein Occlusion (RVO) 
Guidelines July 2015 (Internet) Available from: <https://www.rcophth.ac.uk/standards-
publications-research/clinical-guidelines/> (Accessed 06 Jul 2016). 
Wong TY, Scott IU (2010) Clinical practice. Retinal-vein occlusion. N Engl J 
Med;363(22):2135-44.  
Yasuda M, Kiyohara Y, Arakawa S et al (2010)  Prevalence and systemic risk factors for 
retinal vein occlusion in a general Japanese population: the Hisayama study. Invest 
Ophthalmol Vis Sci;51(6):3205-9. 

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13 
Appendix 1: Clinically notable vital signs 
The criteria for clinically notable abnormal vital signs are shown below. In order to be 
identified as being potentially clinically notable abnormal, an on-treatment vital signs value 
would need to meet the criterion value, and represent a change of at least the magnitude noted 
in the change column. 
Clinically notable abnormal vital signs values for adults 
Variable 
Criterion Value 
Change Relative to Baseline 
Heart Rate 
≥ 120 b.p.m. 
≤ 50 b.p.m. 
increase of ≥ 15 b.p.m. 
decrease of ≥ 15 b.p.m. 
Systolic blood pressure 
≥ 180 mm Hg 
≤ 90 mm Hg 
increase of ≥ 20 mm Hg 
decrease of ≥ 20 mm Hg 
Diastolic blood pressure 
≥ 105 mm Hg 
≤ 50 mm Hg 
increase of ≥ 15 mm Hg 
decrease of ≥ 15 mm Hg 
 

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14 
Appendix 2: Pre-Injection procedures for ranibizumab 
The following procedures (except where noted) will be conducted by the injecting physician 
to assure aseptic conditions: 
1. Before treatment, the patients should be instructed to self-administer antimicrobial drops 
four times daily for three days prior to treatment. 
2. Patients should be sufficiently anesthetized and administered with broad-spectrum 
antimicrobial eye drops before ranibizumab administration. 
3. Intravitreal injection of ranibizumab should be conducted under aseptic conditions: 
• The technician assembles the supplies and prepares a sterile field. Supplies include 
swabs, sterile surgical gloves, sterile pads, pack of sterile cotton-tipped applicators, 
eyelid speculum, sterile ophthalmic drape, topical anesthetic, disinfectant ophthalmic 
solution, subconjunctival anesthetic, ophthalmic broad spectrum antimicrobial 
solution, and injection supplies. 
• The physician is to perform surgical hand and finger disinfection and use sterile 
gloves. 
• Disinfect the periocular skin and eyelid of the study eye in preparation for injection. 
Scrub the eyelid, lashes, and periorbital skin with disinfectant ophthalmic solution 
swabs, starting with the eyelid and lashes and continuing with the surrounding 
periocular skin. Make certain that the eyelid margins and lashes are swabbed, and 
proceed in a systematic fashion, from medial to temporal aspects. 
• Place a sterile ophthalmic drape to isolate the field, and place the sterile speculum 
underneath the eyelid of the study eye. 
• Sterilize the conjunctiva sac of the study eye according to local practice, making sure 
the planned injection site on the conjunctiva has been disinfected. 
• Use a sterile pad in a single wipe to absorb excess liquid and to dry the periocular skin. 
4. Instruct patient to direct gaze away from syringe prior to ranibizumab injection. 

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15 
Appendix 3: Post-Injection procedures for ranibizumab 
Instructions 
1. Immediately following the ranibizumab injection, instill a broad spectrum antimicrobial in 
the study eye. 
2. Discard all syringes and needles in the sharps container. 
3. Seal the study drug kit (including the used vial). 
4. Finger counting will be tested on each patient’s study eye within 15 minutes after each 
injection; hand motion and light perception will be tested when necessary. 
5. Measure the intraocular pressure in the study eye between 15 and 60 minutes following 
the ranibizumab injection. 
6. Intravitreal injection may cause a transient increase in intraocular pressure. After 
ranibizumab administration, the perfusion of the optic nerve head should therefore be 
confirmed and the increase in intraocular pressure should be appropriately managed. 
7. Instruct the patient to self-administer a broad spectrum antimicrobial four times daily for 
three days following each ranibizumab injection. 
8. In addition, any other safety assessments according to local practice will be performed. 
9. If there are no safety concerns following the injection the patient will leave the clinic. If 
any concern or immediate toxicity is noted, the patient will remain at the clinic and will be 
treated according to the Investigator’s clinical judgment. 
10. Contact the patient by telephone for safety evaluations 2 (± 1) days following each study 
visit when study drug is administered. Alternatively, any safety assessments according to 
local practice may be performed. Document the attempts to contact the patient or the visits 
to sites in the patient’s source documents. 

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Appendix 4: Post-treatment procedures for laser 
photocoagulation 
1. Finger counting will be tested on each patient’s study eye within 15 minutes after each 
laser application; hand motion and light perception will be tested when necessary. 
2. Measure the IOP in the study eye following the laser application. 
3. After laser application, the perfusion of the optic nerve head should be confirmed. 
4. In addition, any other safety assessments according to local practice will be performed. 
5. If there are no safety concerns following the laser treatment, the patient will leave the 
clinic. If any concern is noted, the patient will remain at the clinic and will be treated 
according to the investigator’s clinical judgment. 
6. Contact the patient by telephone for safety evaluations 2 (± 1) days following each study 
visit when study treatment is administered. Alternatively, any safety assessments 
according to local practice may be performed. Document the attempts to contact the 
patient or the visits to study sites in the patient’s source documents.