Conditions: Diabetic Retinopathy
Keywords: Diabetic macular edema Visual impairment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 135
Healthy volunteers: no

Brief summary:
The purpose of this study was to demonstrate that the change of best corrected visual acuity (BCVA) was comparable in patients treated with ranibizumab at the discretion of the investigator vs. treatment according to a standard of care scheme (pro re nata, as needed).

Detailed description:

Arms:
arm 1: ranibizumab 0.5 mg, after initial monthly treatment until maximum BCVA and no signs or no further change of disease activity, the investigator treated patients at their own discretion. There were no strict recommendations for retreatment or scheduling of upcoming visits. arm 2: ranibizumab 0.5 mg, after initial monthly therapy until maximum BCVA and no signs or no further improvement of disease activity, patients were monitored every month and retreated if any signs of disease activity occurred

Interventions: intervention 1: ranibizumab 0.5 mg
Intervention descriptions: intervention 1: intravitreal injection

Protocol document:
Prot_000.pdf: 
Clinical Development 
RFB002 (Ranibizumab, Lucentis®) 
Clinical Trial Protocol CRFB002DDE26 / NCT02366468
A 12-months, randomized, VA-assessor blinded, 
multicenter, controlled phase IV trial to investigate non-
inferiority of two treatment algorithms (discretion of the 
investigator vs. pro re nata) of 0.5 mg ranibizumab in 
patients with visual impairment due to diabetic macula 
edema  
Authors: 
 
Document type: 
Clinical Trial Protocol  
EUDRACT number: 
2014-002854-37 
Version number: 
v01 (incl. Amendment 01) 
Development phase: 
IV 
Release date: 
18-04-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NOVDD Template Version 03-Feb-2012 


Novartis 
Confidential 
Page 2 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Summary of protocol amendments ...................................................................................... 9 
Protocol synopsis ............................................................................................................... 12 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 17 
2 
Study objectives ................................................................................................................. 17 
2.1 
Primary and key secondary objectives .................................................................. 17 
2.1.1 
Primary objective .................................................................................. 17 
2.1.2 
Secondary objectives ............................................................................. 17 
 
 17 
3 
Investigational plan ........................................................................................................... 18 
3.1 
Study design........................................................................................................... 18 
3.2 
Rationale of study design ....................................................................................... 19 
3.3 
Rationale of 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 ................................................................................................... 23 
5 
Treatment ........................................................................................................................... 26 
5.1 
Protocol requested treatment ................................................................................. 26 
5.1.1 
Investigational treatment ....................................................................... 26 
5.1.2 
Additional study treatment .................................................................... 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment, randomization ................................................................... 26 
5.4 
Treatment masking ................................................................................................ 27 
5.5 
Treating the patient ................................................................................................ 27 
5.5.1 
Patient numbering ................................................................................. 27 
5.5.2 
Dispensing the investigational treatment .............................................. 27 


Novartis 
Confidential 
Page 3 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
5.5.3 
Handling of study treatment .................................................................. 28 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 30 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 30 
5.5.6 
Rescue medication ................................................................................ 30 
5.5.7 
Concomitant treatment .......................................................................... 31 
5.5.8 
Prohibited Treatment ............................................................................. 31 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 31 
5.5.10 
Emergency breaking of treatment assignment ...................................... 32 
5.5.11 
Study completion and post-study treatment .......................................... 32 
5.5.12 
Early study termination ......................................................................... 33 
6 
Visit schedule and assessments ......................................................................................... 33 
6.1 
Information to be collected on screening failures.................................................. 37 
6.2 
Patient demographics/other baseline characteristics ............................................. 37 
6.3 
Treatment exposure and compliance ..................................................................... 38 
6.4 
Efficacy .................................................................................................................. 38 
6.4.1 
Best corrected visual acuity .................................................................. 38 
6.4.2 
Optical Coherence Tomography ........................................................... 39 
6.4.3 
Color Fundus Photography 
.................. 39 
6.4.4 
Appropriateness of efficacy assessments .............................................. 40 
6.5 
Safety ..................................................................................................................... 40 
6.5.1 
Physical Examination ............................................................................ 40 
6.5.2 
Vital signs.............................................................................................. 40 
6.5.3 
Height and Weight ................................................................................ 40 
6.5.4 
Laboratory evaluations .......................................................................... 40 
6.5.5 
Pregnancy and assessments of fertility ................................................. 40 
6.5.6 
Eye-specific safety monitoring ............................................................. 40 
6.5.7 
Gonioscopy ........................................................................................... 42 
6.5.8 
Hematology ........................................................................................... 42 
6.5.9 
Clinical chemistry ................................................................................. 42 
6.5.10 
Urinalysis .............................................................................................. 42 
6.5.11 
Electrocardiogram (ECG) ..................................................................... 42 
6.5.12 
Appropriateness of safety measurements .............................................. 42 
6.6 
Other assessments .................................................................................................. 42 
6.6.1 
Resource utilization ............................................................................... 42 
 
 43 


Novartis 
Confidential 
Page 4 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
6.6.3 
Pharmacokinetics .................................................................................. 43 
6.6.4 
Pharmacogenetics (optional) ................................................................. 43 
6.6.5 
Other biomarkers ................................................................................... 43 
 
 43 
 
 43 
 
 44 
7 
Safety monitoring .............................................................................................................. 44 
7.1 
Adverse events ....................................................................................................... 44 
7.2 
Serious adverse event reporting ............................................................................. 46 
7.3 
Liver safety monitoring ......................................................................................... 47 
7.4 
Pregnancy reporting ............................................................................................... 47 
8 
Data review and database management ............................................................................. 48 
8.1 
Site monitoring ...................................................................................................... 48 
8.2 
Data collection ....................................................................................................... 48 
8.3 
Database management and quality control ............................................................ 48 
8.4 
Data Monitoring Committee .................................................................................. 49 
8.5 
Adjudication Committee ........................................................................................ 49 
9 
Data analysis ...................................................................................................................... 49 
9.1 
Analysis sets .......................................................................................................... 49 
9.2 
Patient demographics and other baseline characteristics ....................................... 50 
9.3 
Treatments ............................................................................................................. 50 
9.4 
Analysis of the primary variable ............................................................................ 50 
9.4.1 
Variable(s) ............................................................................................. 50 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 51 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 51 
9.4.4 
Supportive analyses ............................................................................... 51 
9.5 
Analysis of secondary and other variables ............................................................ 52 
9.5.1 
Efficacy variables .................................................................................. 52 
9.5.2 
Safety variables ..................................................................................... 52 
Adverse Events .................................................................................................................. 53 
Vital signs and IOP ............................................................................................................ 53 
9.5.3 
Resource utilization ............................................................................... 53 
 
 53 
9.5.5 
Pharmacokinetics .................................................................................. 53 
9.5.6 
Pharmacogenetics .................................................................................. 53 
9.5.7 
Biomarkers ............................................................................................ 54 


Novartis 
Confidential 
Page 5 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
9.5.8 
Pharmacokinetics .................................................................................. 54 
9.6 
Interim analyses ..................................................................................................... 54 
9.7 
Sample size calculation .......................................................................................... 54 
10 Ethical considerations ........................................................................................................ 54 
10.1 
Regulatory and ethical compliance ........................................................................ 54 
10.2 
Informed consent procedures ................................................................................. 54 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 55 
10.4 
Publication of study protocol and results............................................................... 55 
11 Protocol adherence ............................................................................................................ 55 
11.1 
Protocol Amendments ........................................................................................... 56 
12 References ......................................................................................................................... 56 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 59 
14 Appendix 2: PRP (panretinal laser photocoagulation) procedures .................................... 61 
 
List of tables 
Table 6-1 
Assessment schedule ............................................................................. 34 
Table A1-1 
Critical values for vital signs................................................................. 59 
Table A1-2 
Critical values for laboratory values ..................................................... 59 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 19 
 


Novartis 
Confidential 
Page 6 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
List of abbreviations 
AAO  
American Academy of Ophthalmology  
AE 
 
Adverse event 
AMD  
Age related macular degeneration 
ANCOVA 
Analyses of covariance 
BCVA  
Best Corrected Visual Acuity 
BPM  
Beats per minute 
BSL 
 
Baseline 
CRF 
 
Case Report/Record Form (electronic) 
CPO  
Country Pharma Organization 
CRC  
Central Reading Center 
CRO  
Contract Research Organization 
 
 
  
cSLO   
Confocal scanning laser ophthalmoscope 
CSRT  
Central subfield retinal thickness  
DHP  
Data Handling Plan 
DI 
 
Discretion of the investigator  
DME  
Diabetic Macular Edema 
DNA  
Deoxyribonucleic acid 
DR 
 
Diabetic Retinopathy  
DRS  
Diabetic Retinopathy Study 
DS&E  
Drug Safety & Epidemiology 
EDC  
Electronic Data Capture 
EPO 
 
Erythropoietin  
EOS 
 
End of study 
EOT   
End of treatment 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
 
European Union 
 
 
  
FAS 
 
Full analysis set  
FDA  
Food And Drug Administration 
FP 
 
Fundus Photography 
GFR  
Glomerular filtration rate  
HbA1c  
Glycosylated hemoglobin 
hCG  
Human chorionic gonadotropin 
IB 
Investigators Brochure 


Novartis 
Confidential 
Page 7 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
 
Independent Ethics Committee 
IOP 
 
Intraocular pressure 
IRB 
 
Institutional Review Board 
  
 
IRT 
 
Interactive Randomization Technology 
IVT 
 
Intravitreal 
LOCF  
Last observation carried forward 
 
mCNV  
Myopic choroidal neovascularization 
MedDRA 
Medical dictionary for regulatory activities 
NEI 
 
National Eye Institute 
OCT  
Optical coherence tomography 
PDR   
Proliferative Diabetic Retinopathy 
PFS 
 
Pre-filled syringe 
PPS 
 
Per Protocol Set  
PRN  
Pro re nata (as needed) 
PRP 
 
Panretinal Photocoagulation 
RS 
 
Randomized Set 
RVO  
Retinal vein occlusion 
SAE 
 
Serious adverse event 
SCN  
Screening 
SD-OCT  
Spectral domain OCT 
SmPC  
Summary of Product Characteristics 
SOC   
System Organ Class 
SUSAR  
Suspected Unexpected Serious Adverse Reactions 
T&E  
Treat & Extend 
TIA 
 
Transient ischemic attack 
VA 
 
Visual acuity 
VEGF   
Vascular Endothelial Growth Factor 
  
  
VI 
 
Visual impairment 


Novartis 
Confidential 
Page 8 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
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) 
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.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part. 
Period 
A subdivision of a study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
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/ treatment 
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy  
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
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 
 


Novartis 
Confidential 
Page 9 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Summary of protocol amendments 
Amendment 01 
This amendment was issued to stop further recruitment to the study. The reason to stop 
recruitment is new and relevant scientific evidence regarding treatment patterns with 
ranibizumab which does not justify continuing the trial with newly included patients.  
New clinical trials and analyses showed that other ranibizumab treatment approaches than 
PRN for DME are successful (PRN: pro re nata – as needed injections with monthly 
monitoring).  
Already in 2010 first evidence was published in the DRCR.net Protocol I trial (Elman et al. 
2010): The study protocol allowed the extension of monitoring intervals up to 16 weeks after 
the first year of treatment. But also in first year, where monthly visits took place and 
investigators treated the patients as needed, several patients required only very few injections 
(about 25% of patients only needed 4-6 injections) and from week 24 to week 48 the median 
of injections was only 3 (Diabetic Retinopathy Clinical Research et al. 2011). 
In recent published data of RELIGHT study (Pearce et al. 2015) patients were initially treated 
with 3 injections, then monitored monthly for signs of disease activity and treated if needed. 
Beginning with month 6, patients were monitored bimonthly until month 18 and treated with 
ranibizumab as needed showing BCVA gains comparable to other trials like RESTORE with 
monthly monitoring intervals and RETAIN with a Treat and Extend approach. A recent post-
hoc analysis (Framme 2015, Novartis data on file) indicates that in the PRN arms of 
RESTORE and RETAIN studies, there is a broad variance of injection frequency from month 
5 to month 12 leading to the assumption that monitoring intervals for at least some patients 
can be extended quite early: 19.5% of patients did not need any treatment from month 5 to 12, 
9.2% needed only 1, 8.5% of patients only 2 injections.  
In summary these trials and analyses indicate that there is already a strong evidence for 
treating and monitoring DME patients at the discretion of the investigator. 
Because of this evidence no further patients should be randomized to the trial after this 
amendment is effective (after approval of Independent Ethics Committee and Health 
Authorities).  
Although recruitment stops early the data of already randomized patients will be evaluated 
descriptively and compared to the existing evidence. With the results of this (although down-
sized version) clinical trial we aim to further support evidence for a patient-tailored, 
investigator-based approach regarding monitoring and treating patients with visual 
impairment secondary to Diabetic Macular Edema (DME). 
As the current SmPC allows use of ranibizumab as outlined in the DI and PRN arm, already 
randomized patients can remain in the study and be treated according to protocol. The 
interventions are non-invasive or invasive but according to recommendations in the current 
guidelines on DME/Diabetes mellitus treatment, posing no additional risk for patients when 
further observed and treated in this trial (Stellungnahme der Deutschen Ophthalmologischen 
Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbandes der Augenärzte 
Deutschlands, 2013; Matthaei et al. 2011, Landgraf et al. 2015).  


Novartis 
Confidential 
Page 10 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
This amendment will also clarify some aspects of the protocol. Primarily, clarifications have 
been provided around assessing and treating the patient. Also typos and format errors were 
corrected. 
The trial is ongoing (approx. 130 patients enrolled). No impact on the study population or the 
patients’ safety is expected.  
Evaluation of movement patterns, pedometry and genetics were canceled before start of study 
due to technical reasons and therefore sections are deleted in the whole document. No blood 
samples for genetic evaluations were and will, respectively, be obtained in this trial.    
Changes to Section 4.Population: 
– Update of exclusion criterion 20: unfortunately in first protocol version there was no 
difference in pretreatment condition for anti-angiogenic drugs between study eye and 
fellow eye. To reduce unnecessary protocol deviations, that are present at the moment, 
section was updated to change conditions for the fellow eye (prior treatment less than 1 
month)  
Changes to Section 5 Treatment: 
– 5.1.2 and 5.5.3.2.2: indication for panretinal laser photocoagulation was clarified 
– 
 
 
– Chapter 5.5.3.2 was structured and additional information regarding combined treatment 
of laser and ranibizumab was added 
– In chapter 5.5.3.3.1 further recommendations and clarifications for treatment were 
added 
– Clarification on diabetes treatment was moved from chapter 5.5.8 to 5.5.7 
– In chapter 5.5.8 section on concomitant medication was deleted (wrong chapter 
allocation), investigational drugs suspected to influence outcome were added and 
vitrectomy was limited to study eye   
– Chapter 5.5.9 was updated to give further guidance on treatment discontinuation 
Changes to Section 6 Visit schedule and assessments: 
– Chapter 6: a clarification of documentation in DI-arm was added and a reference was 
added that visits can be split to several days  
– Table 6-1 was revised for more convenient reading and updated to reflect the changes in 
protocol (e.g. genetic blood sampling deleted) 
– Chapter 6.3: Information to be collected on previous DME treatments was added and 
recording of concomitant medication was aligned with chapter 5.5.7. 
– Chapter 6.4: clarification was added that imaging at study start needs to be repeated if  
images not eligible 
– 
 
 
– 
 
 
Changes to Section 7 Safety monitoring: 


Novartis 
Confidential 
Page 11 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
– 
Chapter 7.1.: reporting of events after end of study period was aligned with chapter 7.2 
(30 days)  
– 
Chapter 7.2: Period of SAE reporting was clarified 
Changes to Section 9 Data analysis: 
– 
Chapter 9.7. update to take reduced patient number into consideration  
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. 
 


Novartis 
Confidential 
Page 12 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Protocol synopsis  
Protocol number 
CRFB002DDE26 
Title 
A 12-months, randomized, VA-assessor blinded, multicenter, 
controlled phase IV trial to investigate non-inferiority of two 
treatment algorithms (discretion of the investigator vs. pro re nata) 
of 0.5 mg ranibizumab in patients with visual impairment due to 
diabetic macula edema  
Brief title 
Study of efficacy of ranibizumab in different regimens in patients 
with diabetic macula edema (DME) - DIVERSE 
Sponsor and Clinical 
Phase 
Novartis  
Phase 4 study 
Investigation type 
Drug 
Study type 
Interventional  
Purpose and rationale 
The purpose of this study is to demonstrate non-inferiority of 0.5 mg 
ranibizumab in discretion of the investigator (DI) treatment regimen 
compared to 0.5 mg ranibizumab pro re nata (PRN) treatment 
regimen in patients with visual impairment due to DME. DI regimen 
may provide similar visual function benefit as PRN regimen. 
Primary Objective(s) 
and Key Secondary 
Objective 
The primary objective is to demonstrate that the mean average 
change of BCVA in patients with DME treated with ranibizumab 
injections at the discretion of the investigator (DI) and in accordance 
with disease activity criteria is non-inferior to current standard of 
care (PRN). 
Secondary Objectives 
 
To evaluate:  
• Mean change of visual acuity by comparing change of BCVA in 
ETDRS letters between baseline and month 12  
• Frequency of visits and injections, treatment free intervals and 
visit  
• mean change of central subfield retinal thickness (CSRT) and 
foveal center point thickness from baseline will be evaluated by 
central reading center assessing OCT images 
• change in DRS retinopathy scale evaluated by central reading 
center scoring fundus photography 
• Influence of relevant HbA1c-, blood pressure and blood lipid 
levels changes on primary objective (ANCOVA Analysis) 
Study design 
This is a 12-months, phase IV, randomized, parallel-group, visual 
acuity assessor-masked, multi-center, interventional study assessing 


Novartis 
Confidential 
Page 13 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
the efficacy and safety of DI vs. PRN regimens of 0.5 mg 
ranibizumab intravitreal (IVT) injections. Approximately  130 
eligible patients with VI due to DME will be randomized. At the 
baseline visit on day 1, a patient whose eligibility is confirmed will 
be randomized 1:1 into one of the treatment arms.  
Population 
The study will include adult patients with Type 1 or Type 2 diabetes 
mellitus and visual impairment due to diabetic macular edema. A 
total of approximately 130 patients (65 in each treatment arm) will 
be randomized at approximately 30 centers across Germany. 
Patients will be treated in an outpatient setting. 
Inclusion criteria 
• Male or female patients > 18 years of age giving written 
Informed Consent and who are willing and capable to comply 
with all study procedures. 
• Patients with Type 1 or Type 2 diabetes mellitus with 
glycosylated hemoglobin (HbA1c) ≤ 12.0%. 
Inclusion criteria for the study eye at screening: 
• Patients with visual impairment due to DME in at least one eye. 
If both eyes are eligible, the one with the worse visual acuity, as 
assessed at Visit 1, will be selected by the investigator as the 
study eye.  
• BCVA ≥ 24 and ≤ 78 letters in the study eye, using ETDRS-like 
visual acuity testing charts.  
• Concomitant conditions in the study eye are only permitted if, 
they do not prevent improvement of visual acuity on study 
treatment 
Main Exclusion criteria 
Ocular medical history 
• Active intraocular inflammation  
• Any active infection 
• History of uveitis 
• Structural damage within 0.5 disc diameter of the center of the 
macular  
• Patients with both, a BCVA score of > 73 letters and a central 
subfield thickness (CSFT) of < 300 µm in the study eye. 
• Uncontrolled glaucoma  
• Neovascularization of the iris  
• Proliferative vitreoretinopathy in study eye 
• History of retinal detachment, retinal tear or macular hole 
Prior and planned Ocular treatments 
• Any intraocular surgery in the study eye within 4 months prior to 
randomization. 
• Vitrectomy/vitreoretinal surgery  


Novartis 
Confidential 
Page 14 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• Planned medical or surgical intervention 
• Treatment with anti-angiogenetic drugs within 3 months prior 
randomization for study eye and 1 month for fellow eye 
• Intravitreal steroids in phakic eye or without sufficient time 
since last treatment (at least 3 months, for dexamethasone 
implant 6 months or 3 years for fluocinolone implant 
Systemic conditions or treatments 
• History of stroke within 4 months prior to enrollment. 
• Untreated diabetes mellitus. 
• Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg  
• Pregnant and nursing women and women physiologically 
capable of becoming pregnant, unless they are using effective 
methods of contraception 
Investigational and 
reference therapy 
The investigational treatment in this study is 0.5 mg ranibizumab 
10 mg/ml solution for injection, supplied in prefilled syringes (PFS). 
If PFS are not available vials will be used. 
Efficacy assessments 
• Best Corrected Visual Acuity (ETDRS) 
• Spectral Domain Optical Coherence Tomography 
• 
Color Fundus Photography 
Safety assessments 
• Adverse events  
• Vital signs 
• Standard ophthalmic examinations (including ophthalmoscopy, 
slit lamp, intraocular pressure, gonioscopy) 
Key other 
assessments 
• 
 
 
 
 
Data analysis 
The primary objective of this trial is to demonstrate, that the 
ranibizumab treatment at the discretion of the investigator (DI) is 
non-inferior to ranibizumab PRN treatment with respect to the mean 
average BCVA change from baseline to month 12. 
However as the assumed patient number for primary outcome will 
not be reached the data analysis will be purely exploratory. 
The following hypothesis will be tested at a one-sided 0.025 level. 
Non-inferiority with respect to BCVA: 
H0: µDI - µPRN ≤ - ∆ versus HA: µDI - µPRN > - ∆ 
where µDI and µPRN are the unknown mean average changes from 
baseline in BCVA to month 12 in the DI regimen and the PRN 
regimen, respectively. ∆ is the non-inferiority margin and is pre-


Novartis 
Confidential 
Page 15 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
defined to be 4 letters. 
The hypothesis testing with respect to non-inferiority of BCVA will 
be carried out using an analysis of covariance model including 
treatment group and center as factor and baseline BCVA as 
continuous covariat. For the treatment contrast, the point-estimate 
will be given with its (two-sided, 95%-) confidence interval and the 
p-value for the (unshifted) null hypothesis µDI - µPRN = 0. The 
one-sided non-inferiority-p-value for the shifted hypothesis µDI - 
µPRN ≤ - ∆ will be calculated additionally. Non-inferiority will be 
claimed, if the lower limit of the confidence interval does not exceed 
– ∆. 
Key words 
Ranibizumab, diabetic macular edema, discretion of the investigator 
regimen  
 


Novartis 
Confidential 
Page 16 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
1 
Introduction 
1.1 
Background  
Diabetes mellitus (DM) is the most common endocrine disease with prevalence estimates 
ranging between 2 to 5% of the world’s population. Diabetic retinopathy (DR) and diabetic 
macular edema (DME) secondary to DR are common microvascular complications in patients 
with DM and may have a sudden and debilitating impact on visual acuity (VA) (Riordan-Eva, 
2004). 
Vision-threatening DME is characterized by swelling of the central part of the retina and 
arises from breakdown of the blood-retinal barrier (BRB) with subsequent 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) (Aiello 1997) (Vinores 1997). When 
VEGF was measured in eyes of patients with different pathologies involving macular edema, 
patients with DME showed the highest intraocular VEGF concentrations (Campochiaro 
2009). 
Intravitreal injection of a VEGF inhibitor is currently the gold standard treatment for visual 
impairment due to DME followed by laser photocoagulation (Stellungnahme der Deutschen 
Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbandes 
der Augenärzte Deutschlands, 2013, Bandello 2012). 
Different treatment regimens have been tested to reduce visual impairment (VI) due to DME. 
Starting with monthly treatment in clinical studies (Massin et al. 2010; Do et al. 2012; Do et 
al. 2011; Brown et al. 2013; Nguyen et al. 2012), at the moment PRN (pro re nata, as needed) 
treatment with monthly monitoring visits is state of the art which was successfully tested in 
the RESTORE and DRCR.net study (Mitchell et al. 2011; Lang et al. 2013; Schmidt-Erfurth 
et al. 2014; Elman et al 2010, 2011, 2012 and 2015). But more and more data for “treat and 
extend treatment” (T&E) regimen (Prunte et al. 2015 or other schemes have been published 
and are currently under discussion (Korobelnik et al. 2014). RETAIN study has shown that 
monthly monitoring can be extended for certain patients, but mandatory injections in 
RETAIN at every visit lead to more injections than needed compared to PRN treatment 
schemes (RESTORE, RETAIN study). So there is a need for different treatment regimens that 
should also reflect the differences in clinical/office setting, improve patient adherence and 
takes into account disease subtypes and previous therapy. 
As a consequence in this study we want to test an alternative treatment scheme, where the 
investigator decides when to monitor and/or treat the DME patient.  
In addition this study might provide data on predictors by evaluating which patient needs 
more frequent monitoring and which patients need less monitoring. To further broaden the 
knowledge on DME and DR and to better reflect the daily routine in the clinics, patients with 
additional proliferative diabetic retinopathy (PDR) and retinal ischemia will not be excluded.  
This study will also investigate new functional parameters (e.g. microperimetry) optionally at 
equipped centers.  


Novartis 
Confidential 
Page 17 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Meanwhile the label of ranibizumab has been updated with corresponding data and is now 
supporting individualized treatment and monitoring intervals for patients with DME (see 
chapter “Summary of Amendment 01”).    
1.2 
Purpose  
The purpose of this trial is to demonstrate that the change of best corrected visual acuity 
(BCVA) is comparable in patients treated with ranibizumab at the discretion of the 
investigator vs. treatment according to PRN scheme with monthly monitoring. Furthermore 
the number of injections and visits will be compared between treatment groups as well as 
morphologic parameters. Subgroups and new methods will enlarge our knowledge on the 
efficacy of ranibizumab. With the results of this study we aim to present a patient-tailored, 
investigator-based approach to monitor and treat patients with visual impairment secondary to 
Diabetic Macular Edema (DME). 
2 
Study objectives 
2.1 
Primary and key secondary objectives 
2.1.1 
Primary objective 
The primary objective is to demonstrate that the mean average change of BCVA in patients 
with DME treated with ranibizumab injections at the discretion of the investigator (DI) and in 
accordance with disease activity criteria is non-inferior to current standard of care (PRN). 
2.1.2 
Secondary objectives 
To evaluate:  
• Mean change of visual acuity by comparing change of BCVA in ETDRS letters between 
baseline and month 12  
• Frequency of visits and injections, treatment free intervals and visit  
• mean change of central subfield retinal thickness (CSRT) and foveal center point 
thickness from baseline will be evaluated by central reading center assessing OCT images 
• change in DRS retinopathy scale evaluated by central reading center scoring fundus 
photography 
• Influence of relevant HbA1c-, blood pressure and blood lipid levels changes on primary 
objective (ANCOVA Analysis) 


Novartis 
Confidential 
Page 18 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
3 
Investigational plan 
3.1 
Study design 
This is a 12-months, phase IV, randomized, parallel-group, visual acuity assessor-masked, 
multi-center, interventional study assessing the efficacy and safety of DI vs. PRN regimens of 
0.5 mg ranibizumab intravitreal (IVT) injections. Approximately 130 eligible patients with VI 
due to DME will be randomized. The study duration will be up to 13 months:  
• Screening period: to occur between day -28 and day -3, 
• Baseline period: to occur between day -2 and day 1 (HbA1c and CRC check have to be 
present) 
• Treatment period: from baseline (visit 2) to month 11  
• Follow-Up period: from month 11 to month 12 (visit 14) 
At the baseline visit on day 1, a patient whose eligibility is confirmed will be randomized 1:1 
into one of the treatment arms:  
• Arm 1 (discretion of the investigator, DI): Investigational, RFB002, 10 mg/ml  
• Arm 2 (pro re nata, PRN): Standard of Care; RFB002, 10 mg/ml  
 


Novartis 
Confidential 
Page 19 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Figure 3-1 
Study design 
 
3.2 
Rationale of study design 
Ranibizumab 0.5mg has been approved in the EU since 2011 for VI due to DME. The current 
standard of care treatment is PRN treatment with monthly monitoring (Stellungnahme der 
Deutschen Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des 
Berufsverbandes der Augenärzte Deutschlands, 2013, Bandello 2012). Ophthalmologists 
gained experience in treating modalities of DME patient with anti-VEGF therapies based on 
VA-changes and disease activity in the past years.  
In RESTORE study with monthly monitoring and PRN treatment median of injections after 
12 months were 7.0 in both ranibizumab groups (Mitchell et al. 2011). But already in the 
second half of the first year the injection rate decreased to 2.4 and 2.7 in the respective 
ranibizumab arms (Schmidt-Erfurth et al. 2014). After 24 months 11.0 to 11.3 injections were 
needed in both ranibizumab arms (Lang et al. 2013) that corresponds to 2.5 and 3.9 injections 
in the second year. Starting with the second half of the first year, rapidly declining injection 
frequencies over time did not correspond to lesser monitoring visits. Patients were still seen 
on a monthly basis. Therefore we suppose that monitoring intervals can be extended at least 
for some patients.  
To address these disparity between injection frequency and monitoring visits, in the RETAIN 
study a treat and extend (T&E) treatment regimen was evaluated. Primary objective was the 
visual acuity change 12 and 24 months with two T&E treatment arms (ranibizumab with and 
without additional laser photocoagulation) tested against a PRN treatment (ranibizumab mono 
therapy). In this study the T&E arms treatment intervals could be extended by 1 month if 
patient was stable regarding vision to a maximum interval of 3 months between injections. 
T&E regimen were non-inferior to PRN treatment after 12 and 24 months (mean average 
VA assessor masked treatment 
period 
Randomization & first treatment
Screening
period
Day -28 to 
Day -3 
PRN arm 
Day 1 to Day 330
DI arm
 
Baseline 
period
Day -2 to 
Day 1 
Follow-
up 
period 
Day 360
HbA1c and CRC check
have to be present


Novartis 
Confidential 
Page 20 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
change of best corrected visual acuity of 5.9 and 6.1 in T&E arms vs 6.2 in PRN arm; Prunte 
et al.). After 24 months number of visits could be reduced by 40% in T&E arms vs. PRN arms 
(12.8 and 12.5 vs. 20.5 visits) but there were more injections in the T&E arm than in the PRN 
arm (median of 12 in T&E and 10 in PRN arm). Higher injection rate were due to protocol 
requirements, because T&E patients had to be treated at every visit independent of disease 
activity and patients had to visit the center at least every 3 months. Given the low rate of 
retreatment in RESTORE study we suppose that retreatment at every visit when a T&E 
approach is done, probably is not necessary for every patient.  
As a conclusion of both RESTORE and RETAIN study we propose that monitoring visits can 
be reduced by extending monitoring intervals and injections do not have to take place at every 
visit. We suggest that the investigator should decide when to see the patient for the next visit 
and when to treat the patient based on disease activity criteria. 
With this study we want to test the hypothesis that treatment and visit algorithm done at the 
discretion of the investigator (DI) will lead to equal visual gain, when compared with a 
treatment based on the current standard of care (i.e. PRN treatment with monthly monitoring). 
After initial monthly treatment until maximal VA and no disease activity or no further change 
in disease activity in both treatment arms, in the DI arm the following approach for 
monitoring and treatment will be conducted: monitoring intervals will be determined by the 
physician and will be based on disease activity, as assessed by visual acuity and/or 
morphological parameters. Intervals between study visits can be extended up to 3 months. 
Whenever disease activity is present, patients have to be treated. Monitoring for disease 
activity may include clinical examination, functional testing or imaging techniques (e.g. 
optical coherence tomography (OCT) or 
). This approach may lead to 
a reduction of visit frequencies in the DI study arm, where physicians will consider when to 
see the patient for the next visit based on the individual response of the patient. 
A non-inferiority margin of 4 letters was chosen, as it was indicated by the U.S. Food and 
Drug Administration (FDA) in regulatory discussions of Visudyne studies in 2008. In clinical 
practice 5 letters are usually expected to be clinical relevant. Five letters comprise one line on 
the ETDRS eye chart. So choosing the smaller FDA margin of 4 letters will serve both 
regulatory requirements and clinical practice.  
To minimize bias on primary outcome, VA-assessors will be masked to the treatment 
assignment. Therefore at least 2 VA-assessors will alternate on a monthly basis so that it is 
unknown to them if treatment intervals have been expanded. As one scope of the trial is to 
make prolongation of treatment intervals possible, a blinding of patients and physicians would 
lead to a higher frequency of visits for all patients. To avoid the burden of additional visits to 
mask patients and physicians it was decided to omit further masking procedures. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The ranibizumab dose used in this study as intravitreal injection (0.5 mg) was shown to be 
safe and effective in previous approval trials investigating VI due to DME (e.g. RESTORE 
study) and is approved in the EU for treatment of age related macular degeneration (AMD), 
visual impairment due to DME, retinal vein occlusion (RVO) and myopic choroidal 


Novartis 
Confidential 
Page 21 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
neovascularization (mCNV). The comparator arm is the standard of care and treatment is 
according to the current lable of ranibizumab.  
Initial treatment of both arms on a monthly basis until maximum BCVA and disease inactivity 
or no further change in disease activity is reflecting the current guidelines on how to treat 
DME using both functional and morphologic criteria (Stellungnahme der Deutschen 
Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbandes 
der Augenärzte Deutschlands, 2013, Bandello 2012)  
The investigational arm, arm 1 (DI) is offering a treatment arm, where the investigator decides 
when to monitor and to treat the patient according to current visual acuity and disease activity. 
The rationale for this investigational arm is to find the optimal and individual treatment 
regimen based on the DME disease activity of each patient, reducing visits but gaining 
comparable VA outcome. As physicians do have experience with treatment of DME with anti-
VEGF since at least 3 years we assume that this treatment arm is more realistic than complex 
(re-)treatments like the one investigated in the RETAIN study.  
The maximum treatment duration might be 12 months in this study in both treatment arms.  
As primary efficacy endpoint is BCVA local assessors are masked to the treatment 
assignment in order to ensure unbiased evaluation of the primary objective. To further reduce 
bias on secondary and exploratory objectives reading centers are blinded to treatment 
assignment.  
3.4 
Rationale for choice of comparator 
PRN regimen with monthly monitoring with anti-VEGF medication based on VA and disease 
activity is the current standard of care for patients with VI due to DME (Stellungnahme der 
Deutschen Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des 
Berufsverbandes der Augenärzte Deutschlands, 2013, Bandello 2012). Also initial monthly 
therapy to reach maximum VA and disease inactivity or no further change in disease activity 
can be found in these guidelines. After this initial phase, patients will be monitored monthly 
and retreated if disease activity appears (e.g. impairment of VA or worsening of morphologic 
parameters).  
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits  
Clinical experience with ranibizumab in DME has been well documented by several pivotal 
approval studies: the Phase II RESOLVE (CRFB002D2201), and the Phase III RESTORE 
(CRFB002D2301), 
RESTORE 
Extension 
(CRFB002D2301-E1), 
RETAIN 
(CRFB002D2304), REVEAL (CRFB002D2303), and RISE (FVF4170g), and RIDE 
(FVF4168g) (Massin et al 2010, Mitchell et al 2011, Nguyen et al 2012, Lang et al 2013, 
Schmidt-Erfurth et al 2014; Brown et al. 2013; Novartis data on file) in Caucasian, Asian and 
Black patients. In these studies 2023 patients were randomized, of which 1051 were 
successfully treated up to 3 years with 10 mg/ml Ranibizumab for VI due to DME. Another 
major clinical trial conducted by the DRCR.net study group provided further evidence for the 


Novartis 
Confidential 
Page 22 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
efficacy and tolerability of ranibizumab for the treatment of visual impairment due to DME 
(DRCR.net 2010, DRCR.net 2011a, DRCR.net 2012). In this trial 375 of 691 patients were 
randomized to 0.5 mg Ranibizumab treatment. All mentioned trials did not show any new 
safety findings compared to trials in AMD.  
Also several non-interventional studies include patients with visual impairment due to DME 
(about 3700 in studies Luminous, CRFB002A2406 and Ocean, CRFB002ADE18, effective 
June 2014) which are currently still recruiting. 
Weighing the substantial clinical benefit achieved with ranibizumab across multiple clinical 
trials, such as the RESOLVE, RESTORE, RESTORE Extension, REVEAL, RIDE, RISE, 
DRCR.net studies, and the safety profile as observed for up to 36 months, the results of these 
studies support the use of ranibizumab for the treatment of patients with visual impairment 
due to diabetic macular edema (Ranibizumab Investigators Brochure edition 14, December 
2015). 
Intravitreous injections have been associated with endophthalmitis, intraocular inflammation, 
rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Therefore 
proper aseptic injection techniques will be used and patients will be monitored to permit early 
treatment if an infection occurs. 
Transient increases in intraocular pressure (IOP) have been seen within first hour after 
injection of ranibizumab. Sustained IOP increases have also been reported. Therefore, in this 
study pre- and post-injection IOP will be measured, reported and managed appropriately. 
Additionally, perfusion of the optic nerve head will be monitored as needed. 
There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF 
inhibitors. Therefore, patients with known risk factors for stroke, including history of prior 
stroke or transient ischemic attack will be carefully evaluated by their physicians as to 
whether ranibizumab 0.5 mg treatment is appropriate and the benefit outweighs the potential 
risk. This risk to patients in this trial will be also minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring. 
There are no known clinically relevant disadvantages to participate in the study. 
4 
Population 
The study will include adult patients with Type 1 or Type 2 diabetes mellitus and visual 
impairment due to diabetic macular edema. A total of 130 patients (60 in each treatment arm) 
will be randomized at approximately 30 centers across Germany. Patients will be treated in an 
outpatient setting.  
The calculation of the sample size is provided in Section 9.7. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 


Novartis 
Confidential 
Page 23 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Patient 
1. Male or female patients > 18 years of age giving written Informed Consent and who 
are willing and capable to comply with all study procedures. 
2. Patients with Type 1 or Type 2 diabetes mellitus with glycosylated hemoglobin 
(HbA1c) ≤ 12.0% (107 mmol/mol) at screening (Visit 1). 
Inclusion criteria for the study eye at screening: 
 
3. Patients with visual impairment due to DME in at least one eye. If both eyes are 
eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected by 
the investigator as the study eye.  
4. BCVA ≥ 24 and ≤ 78 letters in the study eye, using ETDRS-like visual acuity testing 
charts at a testing distance of 4 resp. 1 meters (approximate Snellen equivalent of 
20/32 to 20/320) at screening.  
5. Concomitant conditions in the study eye are only permitted if, they do not prevent 
improvement of visual acuity on study treatment 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
Patient Compliance/ Administrative 
1. 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 
hCG test. 
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 of study treatment. Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (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 months 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 or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository  


Novartis 
Confidential 
Page 24 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
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. 
Ocular medical history 
3. Active intraocular inflammation (grade trace or above) in either eye at enrollment. 
4. Any active infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis) in either eye 
at the time of enrollment. 
5. History of uveitis (any cause) in either eye at any time. 
6. Structural damage within 0.5 disc diameter of the center of the macular in the study eye 
likely to preclude improvement in visual acuity following the resolution of macular 
edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser 
scar(s). 
7. Patients with both, a BCVA score of > 73 letters and a central subfield thickness (CSFT) 
of < 300 µm in the study eye. 
8. Uncontrolled glaucoma in either eye at screening (IOP > 24 mmHg on medication or 
according to investigator’s judgment). 
9. Neovascularization of the iris in either eye. 
10. Vitreous hemorrhage impairing the adequate diagnosis of DME in the study eye 
11. Evidence of clinically relevant vitreofoveal adhesion in the opinion of the investigator, 
vitreofoveal traction with foveal involvement or epiretinal membrane with foveal 
involvement in the study eye that is likely to prevent improvement of BCVA loss due to 
DME. 
12. Proliferative vitreoretinopathy in study eye 
13. History of retinal detachment, retinal tear or macular hole in the study eye. 
14. Neovascularization covering an area of ≥ 2 disc areas within the macula (defined as area 
with 6mm diameter centered on the fovea), originating either from neovascularization of 
the disc or multiple neovascularization’s elsewhere in study eye 
15. Patients who are monocular or have a BCVA score in the non-study eye (fellow eye) < 24 
letters (approximate Snellen equivalent of 20/320) at Visit 1. 
Prior and planned Ocular treatments 
16. Any intraocular surgery in the study eye within 4 months prior to randomization. 
17. Vitrectomy/vitreoretinal surgery  
a. In the medical history or planned for study eye  
b. planned vitrectomy or vitrectomy in last 3 months in fellow eye 
18. Planned medical or surgical intervention during the 12-months study period likely to 
interfere with study schedule or outcomes. 


Novartis 
Confidential 
Page 25 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
19. Panretinal laser or focal/grid laser photocoagulation in the study eye within 3 months 
prior to randomization unless sufficient documentation of laser photocoagulation in that 
period of time is available. 
20. Treatment with anti-angiogenic drugs  (pegaptanib sodium, anecortave acetate, 
bevacizumab, ranibizumab, VEGF-Trap, etc.)  
• within 3 months prior to randomization for study eye 
• within 1 month prior randomization for fellow eye. 
21. Use of other investigational drugs at the time of enrollment, or within 3 months or 5 half-
lives from enrollment, whichever is longer. 
22. History of intravitreal corticosteroid treatment in phakic study eye. 
23. Intravitreal corticosteroids in post-cataract surgery study eye (aphakic or pseudophakic, 
without damaged posterior capsule) within 3 months or 6 months for dexamethasone 
implant (Ozurdex®) or 3 years for fluocinolone implant (Iluvien®) prior to 
randomization.  
24. Ocular conditions in the study eye that require chronic concomitant therapy with topical 
ocular corticosteroids. 
Systemic conditions or treatments 
25. History of stroke within 4 months prior to enrollment. 
26. Renal failure requiring dialysis or renal transplant. 
27. Untreated diabetes mellitus. 
28. Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg at screening and 
randomization. 
29. Conditions that require chronic concomitant therapy with systemically administered 
corticosteroids. 
30. Current use of or likely need for systemic medications known to be toxic to the lens, 
retina or optic nerve, including Deferoxamine, Chloroquine/ hydroxychloroquine 
(Plaquenil), Tamoxifen, Phenothiazines and Ethambutol. 
31. Use of any systemic anti-VEGF drugs within 3 months prior to Screening (e.g. 
bevacizumab [Avastin®], ziv-aflibercept [Zaltrap®]). 
32. Known hypersensitivity to fluorescein or ranibizumab or any component thereof or drugs 
of similar chemical classes. 
33. Any type of advanced, severe or unstable disease or its treatment, that may interfere with 
primary and/or secondary variable evaluations including any medical condition 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  


Novartis 
Confidential 
Page 26 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
• Ranibizumab/RFB002: 10 mg/ml solution for injection  
Study medication will be supplied in commercially available packaging labeled with “Zur 
klinischen Prüfung bestimmt”. Each vial or pre-filled syringe (PFS) will be labeled with the 
appropriate information. Medication labels will comply with the legal requirements and be 
printed in German. The storage conditions will be described on the label. Study medication 
should not be stored together with commercial Lucentis® to avoid mix up. 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile glass vial or PFS. 
Each vial or PFS contains ranibizumab in an aqueous solution (pH 5.5) with histidine, 
trehalose, and polysorbate 20. The vial and PFS do not contain preservatives and are suitable 
for single use only. Ranibizumab must be stored according to the label instructions and it must 
be kept in a secure locked facility. 
Novartis will provide sufficient supplies of ranibizumab for treatment of the study eye to 
allow for completion of the treatment period. 
5.1.2 
Additional study treatment 
Focal/grid laser can be applied additionally in both arms but earliest at month 3.  
Patients with indication for PRP (e.g. PDR, large non-perfusion areas, severe non-
proliferative diabetic retinopathy) will be treated with additional panretinal photocoagulation 
(PRP) at baseline or at least within 3 months after randomization in both arms. 
Macular ischemia should not be treated with PRP according to already mentioned guidelines.  
For more details please refer to chapter 5.5.3.2 Handling of other study treatment. 
5.2 
Treatment arms 
Patients will be assigned to one of the following “2” treatment arms in a ratio of 1:1: 
• Arm 1 (DI): Investigational, RFB002, 10 mg/ml  
• Arm 2 (PRN): Standard of Care; RFB002, 10 mg/ml 
5.3 
Treatment assignment, randomization  
Randomization will be done within the eCRF. Only after confirmation of the diagnosis by 
CRC the randomization will be possible. At visit 2 an eligible patient will be given the lowest 
available randomization number. This number assigns the patient to one of the treatment 
arms.  
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A 
randomization list will be produced by or under the responsibility of Novartis Biometry using 


Novartis 
Confidential 
Page 27 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
a validated system ensuring assignment of treatment arms to randomization numbers in the 
specified ratio.  
The randomization scheme for patients will be reviewed and approved by a member or 
delegate of the Novartis Biometry Randomization Group. 
5.4 
Treatment masking  
In this study, the visual acuity assessor, who is assessing parameters constituting the primary 
endpoint (BCVA), will be masked to the treatment regimen and will not be allowed to 
perform any additional study tasks which would unmask him/her to study treatment. From 
Visit 2 on the BCVA assessment must be performed before any other assessments, and the 
timing of the BCVA assessment will be recorded in the visual outcome form and archived in 
the source document. At least two different BCVA assessors should be certified for this study, 
who will alternate monthly for BCVA assessment to support masking of treatment regimen. 
 
 
Once the designated roles (masked / unmasked) are determined, the roles cannot be switched 
at any time during the conduct of the study. Every effort must be made to limit the number of 
unmasked study personnel to ensure the integrity of this partly masked study. 
Novartis and Contract Research Organization (CRO) personnel involved with the statistical 
analysis and interpretation of the data and results will be masked until the Database Lock. 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Patient-ID Number which is composed by the site 
number assigned by Novartis and a sequential subject number assigned by the investigator 
(per allocation card or equivalently). Once assigned to a patient, the Patient-ID Number will 
not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the database upon data entry.  
Patients who have signed the informed consent form, but fail to meet eligibility criteria for 
enrollment during the Screening Phase will be deemed screen failures and a reason will be 
documented in the Screening Log CRF. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
Via eCRF each patient will be randomized to one of the two treatment arms. Investigational 
treatment is identical for both arms. 
Ranibizumab medication will be supplied as commercially available packaging of Lucentis® 
with the additional label “Zur klinischen Prüfung bestimmt”. The vial or prefilled syringe will 


Novartis 
Confidential 
Page 28 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
be taken from the labeled commercial package and treatment will be performed. After that the 
empty vial or prefilled syringe will be disposed. The commercial package has to be marked 
with patient number and visit date by the investigator to make drug accountability possible. It 
will be stored at a different place than unused packages and commercial (non-study) packages 
to avoid mix-up. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.  
The storage conditions for study drug will be described on the medication label. 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. 
As commercial package is used medication labels will be in the local language and comply 
with the legal requirements of each country. They will include storage conditions for the 
investigational treatment but no information about the patient.  
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator or Novartis monitor will return all unused investigational treatment, packaging, 
drug labels, 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 other study treatment 
Active laser treatment has to be administered before intravitreal injections if treated at the 
same day. The minimum interval between the two treatments is 30 minutes. 
Laser treatments will be monitored. Details are described in the monitoring plan. 
Subthreshold laser can also be used for laser photocoagulation treatment. 
All laser applications to the patient during the study and if applicable 3 months prior 
screening must be recorded on the Dosage Administration Record CRF. 
5.5.3.2.1 Focal/grid laser photocoagulation 
Focal/grid laser photocoagulation can be applied additionally in both arms but earliest at 
month 3 if investigator is of the opinion that patient will benefit from additional focal/grid 
laser photocoagulation. Focal/grid laser should be applied according common ETDRS laser 
recommendations. Sufficient distance to fovea has to be kept: 
• Laser spots have to be at least 500µm from center of fovea 


Novartis 
Confidential 
Page 29 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• Juxtafoveal lesions should not be treated at initial sessions 
5.5.3.2.2 Panretinal photocoagulation (PRP) 
Patients with indication for panretinal photocoagulation (PRP) (e.g. PDR, large non-perfusion 
areas, severe non-proliferative diabetic retinopathy) will be treated additional with PRP at 
baseline or at least within 3 months after randomization in both arms. 
PRP should be applied according common laser recommendations listed in Appendix 2: PRP 
(panretinal laser photocoagulation) procedures.  
 
5.5.3.3 
Instructions for use of investigational treatment 
5.5.3.3.1 Treatment of study eye 
Arm 1 (DI): after initial monthly treatment until maximum BCVA and no signs or no further 
change of disease activity, investigator will treat patients at own discretion. There will be no 
strict recommendations for retreatment or scheduling of upcoming visits except: 
• patients need to be monitored at least every 3 months 
• patients have to be retreated if any signs of disease activity occur.   
• If relevant* loss of visual acuity is the reason for retreatment, next monitoring visit should 
be scheduled in 4 weeks. 
* Relevant loss is defined as loss of visual acuity with a range outside the daily fluctuation 
of VA in DME patients. E.g. if 3-4 letters loss since last visit is accompanied by fluid in 
OCT it is highly likely that no daily fluctuation is present, but a true loss of BCVA. 
Investigator will decide whether VA-loss is relevant or a daily fluctuation and will 
document the decision and the reasoning in the source data 
Due to flexibility of DI-arm, also treatment schemes like PRN, Treat & Extend or fixed 
dosing are allowed.  
Arm 2 (PRN): investigator will treat patients in a PRN scheme, i.e. after initial monthly 
therapy until maximum BCVA and no signs or no further improvement of disease activity, 
patients will be monitored every month and retreated if any signs of disease activity occur. 
For both treatment arms the following procedures apply:  
Initial monthly therapy for both treatment arms: Beginning at baseline, injections are 
administered monthly until maximum visual acuity is achieved and no signs or no further 
improvement of disease activity are present. 
Disease activity: both functional and morphologic parameters will be taken into consideration 
when defining disease activity. That could for example be: 
• BCVA: change of BCVA 
• OCT: increase of retinal thickness  
• 
/FP/ophthalmoscopy: new signs of DME  
If retreatment due to new disease activity is necessary, treatment should be continued until:  


Novartis 
Confidential 
Page 30 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• maximum BCVA is achieved again or there is no improvement of BCVA compared to 
previous visit  
• there is no further decrease of retinal thickness compared with previous visit 
• there is no further regression and no further perspective of regression of other DME 
characteristics 
  
The interval between 2 ranibizumab injections should not be shorter than 28 days.   
If ranibizumab injection and other visit procedures as per assessment schedule cannot be 
performed on same day, the procedures and injection should be done within three days.   
Administration for ranibizumab injections will follow the procedures described in the 
Lucentis® patient information. 
All dosages dispensed to the patient during the study must be recorded on the Dosage 
Administration Record CRF. 
5.5.3.3.2 Treatment of fellow eye 
Patients, who develop a condition at the fellow eye that, in the investigator’s opinion, 
qualifies for and requires treatment may be treated at the investigator’s discretion according to 
the investigators standard of care. The fellow eye will not be treated with study medication. 
Administration of treatment to the fellow eye must be recorded on the Concomitant 
medication/Significant non-drug therapies page of the CRF (dose, timing and type of 
treatment).  
5.5.4 
Instructions for prescribing and taking study treatment 
Not applicable (ranibizumab is not handed to patients). 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
No adjustments of the ranibizumab dosing regimen described in Section 5.5.3.3.1 will be 
allowed. 
Study drug treatment must be interrupted in case of an acute ocular or periocular infection in 
the study eye. Treatment may be resumed on the next visit, as far as the patient’s condition 
allows. 
These changes must be recorded on the Dosage Administration Record eCRF. 
5.5.6 
Rescue medication 
Rescue medication is not foreseen in this study. 
If after detailed evaluation the therapeutic effect is considered insufficient by either the patient 
or the treating physician, the patient may be withdrawn from the study treatment and is able to 
receive whatever treatment is considered to be necessary (see section 5.5.9).  


Novartis 
Confidential 
Page 31 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded including start and 
stop dates and reason for use. 
The treatment in this study will not replace the standard of care treatment of the underlying 
diabetes mellitus type 1 and type 2. The treatment of diabetes mellitus itself has to be 
continued over the duration of the trial as recommended by the responsible physician. 
5.5.8 
Prohibited Treatment 
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of study (V1). 
Table 5-1 
Prohibited treatment 
Medication/Procedure 
Action to be taken 
Concurrent use of any anti-VEGF agents 
either systemic or in the study eye (only 
permitted in the fellow eye) 
To be recorded as a major protocol 
deviation 
Other 
(investigational) 
drugs 
and 
interventions of any type suspected to 
influence outcome, i.e. which might influence 
the course of the underlying ocular disease or 
the study treatment results, respectively  
To be recorded as major or minor 
protocol deviation and depending on 
intervention study drug discontinuation to 
be considered   
Concurrent use of peribulbar or intraocular 
corticosteroids in study eye 
To be recorded as major protocol 
deviation 
Concurrent use of intraocular corticosteroids 
inserts in study eye 
Discontinuation 
from 
further 
study 
treatment 
Vitrectomy of study eye  
Discontinuation 
from 
further 
study 
treatment 
Systemic medications known to be toxic to 
the lens, retina or optic nerve, including 
Deferoxamine, Chloroquine/ hydroxylchloro-
quine (Plaquenil), Tamoxifen, Phenothiazines 
and Ethambutol 
To be recorded in the eCRF 
Treatment with glitazones or fingolimod 
when newly started during the study period. 
To be recorded in the eCRF 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 


Novartis 
Confidential 
Page 32 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information. Investigational treatment must be discontinued. 
The investigator should discontinue investigational treatment for a given patient and/or 
withdraw the patient from study if, on balance, he/she believes that continuation would be 
detrimental to the patient’s well-being. 
Investigational treatment must be discontinued under the following circumstances:  
• Emergence of the following adverse events: 
• Rhegmatogenous retinal detachment or Stage 3 or 4 macular hole in the study eye 
• Transient ischemic attack (TIA) or a stroke during the study 
• Pregnancy 
• Use of prohibited treatment as per Table 5-1 that should lead to treatment discontinuation 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
 
Patients who prematurely withdraw from the study for any reason, should be scheduled for an 
early exit visit (EOS) as soon as possible, at which time all of the assessments listed in Table 
6-1 will be performed (unless they are pregnant, withdraw informed consent or there is any 
other serious condition that would make visit 14 (EOS) assessments impossible).   
Patients who discontinue investigational treatment should NOT be considered withdrawn 
from the study and the investigator should encourage the patient to continue in the study and 
to return to at least quarterly visits for assessments up until month 12. If a patient withdraws 
from treatment or is withdrawn from treatment by the investigator but remains in the trial, the 
patients should be scheduled for an End of Treatment (EOT) visit as soon as possible, at 
which time all of the assessments listed in Table 6-1 will be performed. If they fail to return 
for these assessments for unknown reasons, every effort should be made to contact them as 
specified in Section 5.5.11. 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by newly 
enrolled patients. 
5.5.10 
Emergency breaking of treatment assignment 
Not applicable due to open label treatment (partly masked trial). 
5.5.11 
Study completion and post-study treatment 
Patients will be discharged from the study after visit 14 (month 12). 
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. This care might 
include treatments as recommended in current guidelines (Stellungnahme der Deutschen 


Novartis 
Confidential 
Page 33 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Ophthalmologischen Gesellschaft, der Retinologischen Gesellschaft und des Berufsverbandes 
der Augenärzte Deutschlands, 2013, Bandello 2012). 
5.5.12 
Early study termination 
The study can be terminated at any time for any reason specified in the clinical trial study 
contract by Novartis. Should this be necessary, the patient should be seen as soon as possible 
and treated for a prematurely withdrawn patient. 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 sponsor will be responsible for informing IRBs 
and/or ECs of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
An “(X)” denotes optional assessments/procedures. All data obtained from the assessments 
listed in Table 6-1 must be supported in the patient’s source documentation.  
Patients should be seen for all visits on the designated day with an allowed “visit window” of 
± 7 days beginning with month 1 (V3) but when intravitreal ranibizumab treatment is done at 
least 28 days have to pass between two ranibizumab injections. 
If ranibizumab injection and other visit procedures as per assessment schedule cannot be 
performed on same day the procedures and injection should be done within three days. 
In the DI-arm the next visit available in the eCRF will be used for documentation, 
independent of the date of visit. Only for EOS/EOT always visit 14/month 12 will be 
documented.  
Patients will be instructed to contact their investigator at any time should they have health-
related concerns and might return for an unscheduled visit. 
If patients refuse to return for assessments or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine the reason. At a 
minimum, patients will be contacted for safety evaluations during the 30 days following the 
last study visit or following the last administration of investigational treatment if there are 
post-treatment follow-up visits (whichever is later), including a final contact at the 30-day 
point. Documentation of attempts to contact the patient should be recorded in the source 
documentation.  


 
 
 
 
Table 6-1 
Assessment schedule 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Period 
SCN 
BSL and treatment 
EOS 
EOT 
Treatment month  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study day 
-28 to – 3# 
-2 
to1# 
30 
(±7) 
60 
(±7) 
90 
(±7) 
120 
(±7) 
150 
(±7) 
180 
(±7) 
210 
(±7) 
240 
(±7) 
270 
(±7) 
300 
(±7) 
330 
(±7) 
360# 
(±7) 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Prior Medication 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
X2 
Serum Lipid Levels 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy Test**** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Gonioscopy* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Intraocular Pressure (independent of 
treatment) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional assessments (both 
arms)** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 35 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Period 
SCN 
BSL and treatment 
EOS 
EOT 
Treatment month  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study day 
-28 to – 3# 
-2 
to1# 
30 
(±7) 
60 
(±7) 
90 
(±7) 
120 
(±7) 
150 
(±7) 
180 
(±7) 
210 
(±7) 
240 
(±7) 
270 
(±7) 
300 
(±7) 
330 
(±7) 
360# 
(±7) 
For patients in arm 2 (PRN) 
 
 
Best-Corrected Visual Acuity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical Coherence Tomography 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photography 
 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ranibizumab therapy*** and 
Intraocular Pressure§ 
 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
HbA1c 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
For patients in arm 1 (DI) 
 
 
 
 
 
Best-Corrected Visual Acuity 
X 
X 
X (mandatory at every visit) 
X 
X 
Ophthalmic Exam  
X 
X 
X (mandatory at every visit) 
X 
X 
Optical Coherence Tomography 
X 
X  
X (mandatory at every visit) 
X 
X 
Color Fundus Photography 
 
 
X 
(X) 
(X)  
X 
X 
 
 
 
 
 
 


Novartis 
Confidential 
Page 36 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Period 
SCN 
BSL and treatment 
EOS 
EOT 
Treatment month  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Study day 
-28 to – 3# 
-2 
to1# 
30 
(±7) 
60 
(±7) 
90 
(±7) 
120 
(±7) 
150 
(±7) 
180 
(±7) 
210 
(±7) 
240 
(±7) 
270 
(±7) 
300 
(±7) 
330 
(±7) 
360# 
(±7) 
Ranibizumab therapy*** and 
Intraocular Pressure§ 
 
X 
X 
Monthly treatment until stable BCVA and no signs or no 
further change of disease activity will be present, thereafter 
treatment at discretion of the investigator but mandatory 
when disease activity is present 
 
 
HbA1c 
X 
should be done about every 3-4 months 
X 
X 
For all patients 
 
Focal/grid laser 
 
Focal/grid laser can be applied additionally in both arms 
but earliest at month 3 (see 5.5.3.2.1) 
 
 
 
 
Concomitant Medication 
X 
X 
X 
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 
Study Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SCN: Screening, BSL: Baseline; EOS: end of study; EOT: end of treatment;(X): 
at the discretion of the investigator; [X]: only after first treatment application  
*unless done 1 month prior V1: then record in eCRF is sufficient 
**at participating centers where equipment is available 
***in both treatment arms: initial monthly therapy until maximum BCVA and/or no 
signs or no further change of disease activity; If ranibizumab injection and other 
visit procedures as per assessment schedule cannot be performed on same day 
the procedures and injection should be done within three days. 
**** For women of childbearing potential urine pregnancy test at screening and 
EOS/early exit; 
§Intraocular pressure should be monitored before and within 15 to 60 minutes 
after treatment 
1 have to be done prior any treatment 
2 at visit 14 only weight will be measured 
# can be split to 2-3 days 


 
 
 
 
6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but are not randomized will have the, 
demographics, reason for failing and SAE data 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 adverse events occurring after first study drug application recorded on 
the Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to first study drug 
application. 
If patient was not eligible for randomization at visit 2 he/she can be rescreened at any time, if 
all in- and exclusion criteria are met. A new informed consent has to be signed, a new patient 
number will be used and all assessments of visit 1 have to be retaken. 
6.2 
Patient demographics/other baseline characteristics 
The following information will be collected/documented at screening (V1) and/or baseline 
(V2) for each patient: 
• Year of birth  
• Sex 
• Race 
• Study eye 
• Past medical history and current medical conditions 
• Vital signs 
• HbA1c  
• Serum Lipid Levels 
• Pregnancy testing for women of child-bearing potential 
• Concomitant medications 
• DME characteristics (e.g. thickness at the center subfield, evaluated by OCT, 
 FP 
 
 
• 
 
• BCVA 
• Intraocular pressure 
• Infection status by using slit lamp examination 
• Exclusion of rubeosis iridis (Gonioscopy) 
• Smoking history 
• 
 


Novartis 
Confidential 
Page 38 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• 
 
6.3 
Treatment exposure and compliance 
Any deviations from the protocol in the administration of the ranibizumab injections must be 
described on the Dosage Administration Record of the eCRF. 
With regard to concomitant medications (and, where applicable, the information for which 
eye), the type, reason for use, start date,  stop date (or ‘ongoing’) of medications used after 
enrollment  or during the study will be collected on the Concomitant medications/Significant 
non-drug therapies page of the eCRF. Furthermore history of treatment for DME (e.g. anti-
VEGF, laser photocoagulation, intravitreal steroids) in the last 5 years will also be collected in 
Concomitant medications/Significant non-drug therapies page of the eCRF.  
6.4 
Efficacy 
All efficacy assessments are to be done on the study eye and recorded in the eCRF. Efficacy 
assessments will include both functional and anatomical evaluations. The methods of 
evaluation and the primary, secondary and exploratory parameter to be assessed are listed 
below: 
• Best Corrected Visual Acuity (ETDRS) 
• Spectral Domain Optical Coherence Tomography 
• 
Color Fundus Photography (FP) 
General notes: 
If SD-OCT 
 or FP images are not eligible on V1, the image has to be retaken during 
Screening Phase (unscheduled visit) and the new pictures have to be uploaded for assessment. 
This procedure must be repeated until images are eligible. If eligible pictures cannot be 
obtained within 28 days during screening period, rescreening of the patient has to be done 
with all procedures of visit 1. 
6.4.1 
 Best corrected visual acuity  
BCVA assessment has to be performed at every visit before any procedure takes place 
requiring pupil dilation (i.e. SD-OCT, color fundus photography and 
 
.  
BCVA will be tested using the ETDRS visual acuity testing protocol. VA measurements will 
be taken in a sitting position at an initial test distance of 4 meters using ETDRS charts. The 
overall BCVA score will be calculated using the BCVA worksheet which will be kept in the 
source data and recorded in the eCRF.  


Novartis 
Confidential 
Page 39 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• BCVA will be assessed on the study eye at every visit as per Table 6-1.  
• BCVA will be assessed on the fellow eye at screening (Visit 1), EOT and at the end of 
study visit (V14).  
The site’s staff performing the VA assessments will be certified prior study start by VA 
certifiers. A Study Operations manual for performing VA examinations and a BCVA 
worksheet to calculate overall BCVA score will be provided to each investigative site. 
6.4.2 
Optical Coherence Tomography 
SD-OCT will be assessed in the study eye at every scheduled visit (Table 6-1). Fellow eye 
will be assessed at screening visit and at EOS (month 12)/EOT. The images will be filed in 
the source data. These assessments will be performed by trained technician or investigator at 
the sites and should be performed prior to any investigational drug administration. Image of 
screening visit will be evaluated by CRC (central reading center) for patient eligibility. 
Investigators will evaluate the OCT to assess the status of disease activity. The OCT device 
used for an individual patient must not change during the study. 
Novartis requires certification for OCT evaluation. An operations manual and training 
materials for the certification will be provided by the central reading center. Certification will 
occur prior to any evaluation of study patients. 
The images will be independently reviewed by a CRC, to ensure a standardized evaluation 
and will transfer the data to be used for the statistical analysis to Novartis or CRO. For further 
procedural details, the investigator should refer to the Study Manual provided by the CRC. 
6.4.3 
Color Fundus Photography 
  
An operations manual and training materials will be provided by the central reading center.  
Patients must be assessed using the same camera throughout the course of the study. 
These assessments will be performed by a trained technician at the sites at least at screening, 
EOT and at the end of study for all patients in study eye and the images will be sent to a CRC. 
At all other scheduled visits if the investigator is of the opinion to take 
/FP images they 
should be done as described in the manual. These images will also be provided to the Reading 
center. 
The images independently will be reviewed by the CRC to ensure a standardized evaluation 
and the data for the statistical analysis will be transferred to Novartis or CRO. For further 
procedural details the investigator should refer to the Study Operations Manual provided by 
the CRC. 


Novartis 
Confidential 
Page 40 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
6.4.4 
Appropriateness of efficacy assessments  
The selected efficacy assessments are those used in the clinical practice to assess the 
functional and anatomical changes of the affected macular area due to DME. 
6.5 
Safety 
Safety assessments will consist of monitoring and recording of all AEs and SAEs, ophthalmic 
examinations, IOP by tonometry, vital signs and laboratory values. 
The standard ophthalmic examinations are listed in paragraph 6.5.6. 
Significant findings that are present prior signature of the informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s CRF. 
Significant findings made after first study treatment which meet the definition of an AE must 
be recorded on the AE page of the patient’s CRF. 
6.5.1 
Physical Examination 
Not applicable.  
6.5.2 
Vital signs 
Vital signs will be measured at Screening, Baseline, EOT and visit 14 (EOS): patient’s sitting 
blood pressure (systolic/diastolic measurement in mmHg) and pulse (beats per minute-bpm). 
If the investigator is of the opinion that blood pressure is too high because due to the agitation 
of the patient, measurements may be repeated up to three times. The results will be entered 
into eCRF. Clinically notable vital signs are defined in Appendix 1. 
6.5.3 
Height and Weight 
Height in centimeters (cm) will be measured at visit 1. 
Body weight (in indoor clothing, but without shoes) will be measured at visits 1, EOT and at 
visit 14. 
6.5.4 
Laboratory evaluations 
Blood sampling will be performed at the visits indicated in Table 6-1. The results (HbA1c and 
lipid levels) from the central lab will be recorded. Clinically notable values are defined in 
Appendix 1, Table A1-2.  
6.5.5 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a urine pregnancy test at 
screening (visit 1), EOT and at the end of study (visit 14 or early exit). Results will be 
recorded in the respective CRF. Urine testing sticks will be provided by Novartis for analysis 
of the urine.  
6.5.6 
Eye-specific safety monitoring 
The standard ophthalmic examinations include slit lamp examination, anterior chamber 
examination, direct and indirect ophthalmoscopy of the macular and peripheral retina, and 


Novartis 
Confidential 
Page 41 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
tonometry. They will be performed at every visit as indicated in Table 6-1. Slit lamp and 
fundus examinations will be performed prior to treatment with ranibizumab. 
The test results will be recorded in the source documents and clinically significant 
abnormalities will be recorded on the medical/ocular history page (if occurring before BSL) 
and if occurring after the first injection with investigational drug, on adverse event page of the 
CRF. 
6.5.6.1 
Anterior segment biomicroscopy (slit lamp examination) 
At every scheduled visit, the anterior segment’s structures of the study eye will be carefully 
examined. If needed, an additional examination will be performed after application of any 
study medication. Fellow eye will be examined only at screening, EOS and EOT (if 
applicable) and during the study on discretion of the investigator. 
6.5.6.2 
Ophthalmoscopy 
At visit 1 the posterior segment of both eyes will be examined by the investigator on dilated 
pupil using adequate ophthalmoscopy apparatus in order to confirm the clinical findings 
compatible visual impairment due to DME as inclusion criteria’s assessments. Also a careful 
examination of the peripheral retina must be conducted to ensure that the intravitreal injection 
can safely be performed (i.e. iatrogenic retinal detachment, should not be receive intravitreal 
injections).  
At the indicated visits from baseline (visit 2) on, assessment of the posterior of the study eye 
will be performed and recorded by the investigator and an additional examination if needed 
will be performed after the application of the study medication. If the patient experiences 
blurred vision and light flashes at any time, the investigator should perform the indirect 
ophthalmoscopy examination in order to detect any AEs and apply the appropriate treatment. 
In case of uncertainty regarding the clinical findings at the macular area with 
ophthalmoscopy, a complementary examination using a suitable lens through slit lamp 
apparatus can be done for the study eye by the investigator.  
6.5.6.3 
Intraocular pressure (IOP) 
Both eyes IOP will be measured at Screening and End of Study/early exit visit. Pre-dose IOP 
in the study eye will be assessed by the investigator or trained technician at every scheduled 
visit as from Visit 2 (Day 1) as indicated in the assessment table and post-dose IOP will be 
assessed 15 – 60 min after injection in the study eye. The values will be recorded in mmHg 
and will be entered into the eCRF. 
In case intraocular pressure is ≥25 mmHg in the study eye, and if not transient, for any reason 
and at any time during the study period, treatment and closer monitoring of IOP should be 
performed by the investigator in order to achieve similar values to the baseline measurement. 
In this case, intravitreal procedure is not recommended unless normalization of the IOP has 
been achieved. The investigator should treat appropriately the increased IOP in order to allow 
the patient to continue in the study. 
In addition, at the discretion of the investigator and/or according to the local 
requirements/practices, monitoring of optic nerve head perfusion may be appropriate within 


Novartis 
Confidential 
Page 42 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
30 minutes after injection. Results of these procedures will be recorded in the source 
documents. Only if the findings constitute an AE they have to be recorded in the AE eCRF. 
6.5.7 
Gonioscopy 
Gonioscopy has to be performed on both eyes to exclude rubeosis iridis at screening visit, 
EOT and to check status at visit 14. If last gonioscopy was performed 1 month prior screening 
visit it need not be to be performed on visit 1. When done at visits it should be done after all 
other eye procedures were done, if necessary a visit outside the schedule can be performed 
within one week. 
6.5.8 
Hematology 
Not applicable 
6.5.9 
Clinical chemistry 
Not applicable  
6.5.10 
Urinalysis 
Not applicable  
6.5.11 
Electrocardiogram (ECG) 
Not applicable 
6.5.12 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
6.6.1 
Resource utilization 
Not applicable 


Novartis 
Confidential 
Page 43 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
6.6.3 
Pharmacokinetics 
Not applicable 
6.6.4 
Pharmacogenetics 
Not applicable 
  
6.6.5 
Other biomarkers 
Not applicable 


Novartis 
Confidential 
Page 44 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a subject or 
clinical investigation subject after start of study treatment for participation in the study.  


Novartis 
Confidential 
Page 45 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
The occurrence of adverse events should 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, laboratory test, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant that lead to discontinuation of study drug,  
• they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline 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 adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
• the severity grade   
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study treatment (no/yes) or the injection procedure (no/yes) or the 
other study treatment (non-investigational) (no/yes), 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
• whether it constitutes a serious adverse event (SAE)  
• action taken regarding study treatment  
• whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event (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: 


Novartis 
Confidential 
Page 46 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• 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  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF.  
Once an adverse event 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 treatment/ 
injection procedure/ non-investigational study treatment, 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 Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period up to 30 days) that the patient, or the patient’s personal physician, 
believes might reasonably be related to study treatment. This information should 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 event reporting 
To ensure patient safety, every SAE, regardless of 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 the 30 days period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.  


Novartis 
Confidential 
Page 47 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to study treatment, complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours after awareness of the SAE to the local 
Novartis Drug Safety and Epidemiology Department. The telephone and fax number of the 
contact persons in the local department of Drug Safety and Epidemiology, specific to the site, 
are listed in the investigator folder provided to each site. The original copy of the SAE Report 
Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site. Follow-up information should be provided using a new paper SAE Report 
Form stating that this is a follow-up to a previously reported SAE 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
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 investigational treatment a Drug Safety 
and Epidemiology 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 
investigational 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 Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
Not applicable 
7.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment  


Novartis 
Confidential 
Page 48 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
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 CRFs 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 CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that investigational treatment 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 CRFs must be traceable to these source documents in the patient's file. The investigator 
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 CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs 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 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data.  


Novartis 
Confidential 
Page 49 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies, medical history and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples, FP-, 
 OCT-data and optional evaluations 
 
will be processed centrally and the 
results will be sent electronically to Novartis (or designated CROs). 
At the conclusion of the study, the occurrence of relevant protocol deviations will be 
determined. After these actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Trial Statistician and Statistical Reporting and the Clinical 
Trial Leader. 
8.4 
Data Monitoring Committee 
Not applicable 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis 
All analyses will be performed by Novartis personnel or a designated CRO.  
Descriptive statistics include n, mean, standard deviation, median and ranges for continuous 
variables and frequencies and percentages for categorical variables and will be provided by 
treatment arm unless otherwise specified. 
As baseline value the last assessment collected prior to start of treatment will be considered 
(i.e. data from screening or baseline). 
Further technical details will appear in the Statistical Analysis Plan, which will be finalized 
prior to database lock. 
9.1 
Analysis sets 
The Randomized Set (RS) will consist of all patients who were randomized to one of the 
treatment arms and who received at least one application of study treatment. 
The Full Analysis Set (FAS) will consist of all patients as randomized who received at least 
one application of study treatment and have at least one post-baseline assessment for the 
primary endpoint, i.e. BCVA assessment was performed. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment assigned. 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 study 
treatment as randomized and completed the treatment phase of the trial without major 
protocol deviations. 


Novartis 
Confidential 
Page 50 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Criteria that are assumed to have such an impact will be defined in the data handling plan 
(DHP) and in the Data Review Meeting and documented on the protocol before unmasking. 
The Safety Set will consist of all patients from the RS who had at least one post - baseline 
safety assessment. Patients will be analyzed according to treatment received. The statement 
that a patient had no adverse events also constitutes a safety assessment. 
9.2 
Patient demographics and other baseline characteristics 
Descriptive statistics will be provided for patient demographics and all baseline characteristics 
(including the baseline values of the main efficacy endpoints). 
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
tabulated by system organ class 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 all randomized subjects. 
9.3 
Treatments 
Investigational Treatment 
Descriptive statistics will be provided for exposure to investigational treatment using the 
Safety Set. The number of ranibizumab injections will be presented by treatment arm in 
frequency tables and cumulatively. For the optional re-treatments, the number of re-
treatments, the time to first re-treatment and the proportion of patients with a treatment-free 
interval of at least 3 months will be calculated. 
Additional study treatment:  
The number and percentage of other study treatment (including laser treatment) will be 
presented by treatment arm in frequency tables by visit and cumulatively.   
Concomitant therapies 
The number and percentage of patients taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary using the Safety Set. 
Summaries will be presented separately for prior medications (received prior to the start of 
study) and for concomitant medications (received during the study). 
9.4 
Analysis of the primary and key secondary variable(s) 
The primary objective is to demonstrate that the mean average change of BCVA, averaged 
over all post-baseline visits, in patients with DME treated with ranibizumab injections at the 
discretion of the investigator (DI) and in accordance with disease activity criteria is non-
inferior to current standard of care (PRN). 
9.4.1 
Variable(s) 
The primary variable of this study is the mean average change of BCVA in ETDRS letters 
from baseline to month 12, averaged over the individual changes in BCVA (differences in 
letters) from baseline to all post-baseline visits. The primary analysis will be performed on the 
FAS using the LOCF approach for imputing missing data. However, since this is a non-


Novartis 
Confidential 
Page 51 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
inferiority-trial, the corresponding results obtained for the PPS are regarded as of almost equal 
importance for the interpretation.  
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of this trial is to demonstrate, that the ranibizumab treatment at the 
discretion of the investigator (DI) is non-inferior to ranibizumab PRN treatment with respect 
to the mean average BCVA change from baseline to month 12. 
The following hypothesis will be tested at a one-sided 0.025 level. 
Non-inferiority with respect to BCVA: 
H0: µDI - µPRN ≤ - ∆ versus HA: µDI - µPRN > - ∆ 
where µDI and µPRN are the unknown mean average changes from baseline in BCVA to 
month 12 in the DI regimen and the PRN regimen, respectively. ∆ is the non-inferiority 
margin and is pre-defined to be 4 letters (see section 3.2 for the justification of the margin). 
The hypothesis testing with respect to non-inferiority of BCVA will be carried out using an 
analysis of covariance model including treatment group and center as factor and baseline 
BCVA as continuous covariat. For the treatment contrast, the point-estimate will be given 
with its (two-sided, 95%-) confidence interval and the p-value for the (unshifted) null 
hypothesis µDI - µPRN = 0. The one-sided non-inferiority-p-value for the shifted hypothesis 
µDI - µPRN ≤ - ∆ will be calculated additionally. Non-inferiority will be claimed, if the lower 
limit of the confidence interval does not exceed – ∆. (Please notice that the lower limit of a 2-
sided, 95% confidence interval is identical to the lower limit of a 1-sided, 90% confidence 
interval which is usually used to assess non-inferiority). 
9.4.3 
Handling of missing values/censoring/discontinuations 
For the FAS, the analysis will follow a LOCF (Last Observation Carried Forward) approach 
with the specification that monotone missing values will be replaced by the last post-baseline 
observation prior to the missing time-point. Intermittent missing data will be replaced by the 
mean of the closest non-missing adjacent values. 
9.4.4 
Supportive analyses 
The primary analysis will be repeated for the PPS using the same model as the one used for 
the primary analysis. 
The change from baseline in BCVA will be compared between the two treatments based on 
the assumption of a “Missing at Random (MAR)” process, i.e. assuming that the statistical 
behavior of a patient who drops out post-withdrawal is the same as that for a patient 
remaining in the study and sharing the same covariates and the same measurement history. 
Gender subgroup analysis will be done for primary objective and key secondary objectives. 
 
 
and 


Novartis 
Confidential 
Page 52 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
 
  
In case of significant outliers or deviations from normality assumptions, a nonparametic 
comparison (Wilcoxon Test) may be performed additionally to the primary analyses. 
Further details about the models and analyses will be given in the statistical analysis plan. 
Any major discrepancies in the results across analyses will be investigated as needed. 
9.5 
Analysis of secondary and other variables 
9.5.1 
Efficacy variables 
The analysis of the secondary efficacy objectives will focus on the study eye only and it will 
be based on the FAS. 
At all the time points assessed, each efficacy variable will be presented graphically (where 
appropriate) and descriptive statistics provided based on absolute values and changes from 
baseline. 
Of note is that for patients randomized to the DI, no monthly visit and consequently no 
monthly reporting schedule exists. Therefore efficacy data collected by visit will be described 
on a bi-weekly schedule for the DI arm. Furthermore and in order to allow for a visualization 
of data of both arms on a monthly basis, data collected in between two monthly visits (e.g. at 
Month 5.5) will be reported at the following monthly visit. 
For continuous and ordered categorical variables, changes from baseline will be compared 
between treatment groups using ANCOVA models (with the baseline covariate)/ T-test. For 
treatment differences, 95% confidence intervals will be calculated for differences of means 
(based on ANCOVA models). 
Secondary Efficacy variables 
The variables related to the secondary objectives are described below: 
1. Mean change from baseline in BCVA from baseline to month 12. 
2. Number visits and injections, and treatment free intervals 
3. Changes in central subfield retinal thickness (CSRT) and foveal center point thickness by 
SD-OCT. 
4. Comparison of changes of 1,2 or more steps in DRS retinopathy scale between treatment 
arms compared to baseline 
5. ANCOVA analysis of primary outcome with the additional covariates “relevant changes 
of HbA1c, blood pressure, lipid level” 
9.5.2 
Safety variables 
Safety parameters will include adverse events, the results of ophthalmic examinations, IOP, 
vital signs, and laboratory results. 
All safety analyses will be performed using the Safety Set. 


Novartis 
Confidential 
Page 53 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Adverse Events 
Adverse events will be deemed treatment emergent if the onset date is on or after the date of 
first treatment with investigational drug. Any adverse events recorded prior to the start of 
investigational drug will be listed together with all other adverse events. Only treatment 
emergent adverse events will be summarized. 
Adverse events will be summarized by presenting for each treatment group the number and 
percentage of patients having any adverse event, having an eye-related adverse event, having 
an adverse event in each primary system organ class and having each individual adverse event 
based on the preferred term. Patients who experienced multiple adverse events for a preferred 
term will be counted once, similarly for patients with multiple adverse events per system 
organ class. Eye-related adverse events (as identified by the investigator) will be presented 
separate for the study eye and the fellow eye. Ocular AEs that were recorded in both eyes will 
be reported for each eye separately. 
All other information collected (e.g., severity or relationship to study treatment) will be 
tabulated and listed as appropriate. Summary tables will also be presented for the subset of 
adverse events suspected to be treatment related. 
Deaths, serious adverse events, and adverse events leading to discontinuation of study 
treatment will be listed separately and, if appropriate, summarized by primary system organ 
class and preferred term.  
Vital signs and IOP 
Vital signs will be summarized by presenting shift tables using extended normal ranges with 
thresholds representing clinical relevant abnormality (Appendix 1) and by presenting 
descriptive statistics of raw data and change from baseline. Values outside the extended 
normal range will be listed by patient and treatment group and flagged in data listings. IOP 
measurements will be presented descriptively (absolute values and change from baseline). 
9.5.3 
Resource utilization 
Not applicable. 
9.5.5 
Pharmacokinetics 
Not applicable 
9.5.6 
Pharmacogenetics 
Not applicable 


Novartis 
Confidential 
Page 54 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
9.5.7 
Biomarkers 
Not applicable 
9.5.8 
Pharmacokinetics 
Not applicable 
9.6 
Interim analyses 
No interim analyses will be performed. 
9.7 
Sample size calculation 
A sample size of 133 patients per treatment arm will have 90% power to establish non-
inferiority at a margin of 4 letters for the 0.5 mg ranibizumab “at investigators discretion” 
dosing regimens in comparison to 0.5 mg ranibizumab PRN in the mean average change in 
BCVA based on a one-sided 0.025 significance level, assuming a treatment difference of 0 
letters, a standard deviation of 10 letters and an underlying normal distribution for an 
unstratified t-Test (nQuery Advisor 7.0).   
The Phase III study (RESTORE) results in the FAS suggest a mean average change in BCVA 
of 6 letters with a standard deviation of about 7-8 letters for ranibizumab. To account for 
some more variability related to the retreatment concepts and subgroup treated with additional 
PRP laser in this study as compared to RESTORE, a standard deviation of 10 letters is 
assumed. To account for some drop outs 150 patients will be randomized per treatment arm. 
Due to reasons mentioned in section “Summary of protocol amendments” recruitment will be 
terminated, resulting in a reduced sample size present for analysis.  
As a consequence results are to be interpreted in a purely descriptive manner. With an 
estimate of about 120-150 patients to be enrolled by end of recruitment the expected power 
would be about 55-60% and will be evaluated accordingly.       
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented 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 Code of Federal Regulations Title 
21, and 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 incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 


Novartis 
Confidential 
Page 55 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 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 an informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is approved by the 
IRB/IEC.  
Women of child bearing potential should be informed that application of study treatment 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 or longer, if applicable. 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 
The protocol and the informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
(IRB/IEC) before study start. A signed and dated statement that the protocol and informed 
consent have been approved by the IRB/IEC must be given to Novartis before study initiation. 
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 Clinical 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. 
11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 


Novartis 
Confidential 
Page 56 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. 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, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.  
12 
References 
Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, 
Jirousek M, Smith LE, King GL: Vascular endothelial growth factor-induced retinal 
permeability is mediated by protein kinase C in vivo and suppressed by an orally effective 
beta-isoform-selective inhibitor. Diabetes 46:1473-1480, 1997 
American Diabetes Association (2014) Diagnosis and Classification of Diabetes Mellitus. 
Diabetes Care, vol. 37, (Suppl. 1), p.81-90 
Bandello F, Cunha-Vaz J, Chong NV, Lang GE, Massin P, Mitchell P, Porta M, Prunte C, 
Schlingemann R, Schmidt-Erfurth U (2012) New approaches for the treatment of diabetic 
macular oedema: recommendations by an expert panel. Eye (Lond) 26:485-493 
Brown DM et al. (2013) Long-term Outcomes of Ranibizumab Therapy for Diabetic Macular 
Edema: The 36-Month Results from Two Phase III Trials: RISE and RIDE. Ophthalmology 
120(10): 2013-22Campochiaro PA, Choy DF, Do DV, et al. (2009) Monitoring ocular drug 
therapy by analysis of aqueous samples. Ophthalmology, vol. 116 (11), p.2158-64 
Diabetic Retinopathy Clinical Research net al. 2011. Rationale for the diabetic retinopathy 
clinical research network treatment protocol for center-involved diabetic macular edema. 
Ophthalmology 118: e5-14 
Do DV et al. (2012) One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes 
with diabetic macular edema. Ophthalmology 119.8: 1658-65 
Do DV et al. (2011) The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in 
patients with diabetic macular edema. Ophthalmology 118.9: 1819-26 
Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL, III, 
Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK: Randomized trial 


Novartis 
Confidential 
Page 57 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for 
diabetic macular edema. Ophthalmology 117:1064-1077, 2010 
Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, III, Friedman SM, Glassman AR, Scott 
IU, Stockdale CR, Sun JK: Expanded 2-year follow-up of ranibizumab plus prompt or 
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 
118:609-614, 2011 
Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL, III, Glassman AR, Maturi 
RK, Melia M: Intravitreal ranibizumab for diabetic macular edema with prompt versus 
deferred laser treatment: three-year randomized trial results. Ophthalmology 119:2312-2318, 
2012 
Elman MJ, Ayala A, Bressler NM, Browning D, Flaxel CJ, Glassman AR, et al. Intravitreal 
Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year 
randomized trial results. Ophthalmology 122(2):375-81, 2015 
Framme C, Margaron P, Hashmonay R, Eter N (2015) Ranibizumab 0.5 mg injections 
required within the first year of a flexible treatment regimen in diabetic macular edema 
patients: a post-hoc analysis of RESTORE and RETAIN. IOVS. 56(7):1739 
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, Midena E, Kaiser 
PK, Terasaki H, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter 
T, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Zeitz O, Metzig C, Brown DM: Intravitreal 
Aflibercept for Diabetic Macular Edema. Ophthalmology 121(11):2247-54, 2014 
Landgraf R. et al. Praxisempfehlungen DDG/DGIM Diabetologie 2015; 10 (Suppl 2): S140–
S151 [cited 06.04.2016] available from: http://www.deutsche-diabetes-
gesellschaft.de/fileadmin/Redakteur/Leitlinien/Praxisleitlinien/2015/DuS_S2-
15_Herr_Jannaschk_S140-S151_Landgraf_Typ-2-Diabetes.pdf 
Lang, GE et al. (2013) Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic 
Macular Edema: Interim Analysis of the RESTORE Extension Study. Ophthalmology 
120(10): 2004-12 
Massin P. et al. (2010) Safety and efficacy of ranibizumab in diabetic macular edema 
(RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II 
study. Diabetes Care 33.11: 2399-405 
S. Matthaei, M. Kellerer (Hrsg.): Methodenreport zur Aktualisierung der S3-Leitlinie 
Therapie des Typ-1-Diabetes 2011, [cited: 06.04.2016] available from: http://www.deutsche-
diabetesgesellschaft.de/fileadmin/Redakteur/Leitlinien/Evidenzbasierte_Leitlinien/Methodenr
eport_S3-LL_Therapie_des_Typ-1-Diabetes.pdf 
Mitchell P et al. (2011) The RESTORE study: ranibizumab monotherapy or combined with 
laser versus laser monotherapy for diabetic macular edema. Ophthalmology 118.4: 615-25 
Nguyen Q D et al. (2012) Ranibizumab for diabetic macular edema: results from 2 phase III 
randomized trials: RISE and RIDE. Ophthalmology 119.4: 789-801 


Novartis 
Confidential 
Page 58 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Pearce I et al. (2015) Ranibizumab 0.5 mg for Diabetic Macular Edema with Bimonthly 
Monitoring after a Phase of Initial Treatment: 18-Month, Multicenter, Phase IIIB RELIGHT 
Study. Ophthalmology 122: 1811-1819. 
Prunte C, Fajnkuchen F, Mahmood S, Ricci F, Hatz K, Studnicka J, Bezlyak V, Parikh S, 
Stubbings WJ, Wenzel A, Figueira J, and the RSG (2015) Ranibizumab 0.5 mg treat-and-
extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. doi: 
10.1136/bjophthalmol-2015-307249 
Riordan-Eva P. (2004) Clinical assessment of optic nerve disorders. Eye, vol. 18 (11), p.1161-
8 
Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner O, 
Bouazza AS, Shen H, Osborne A, Mitchell P: Three-Year Outcomes of Individualized 
Ranibizumab Treatment in Patients with Diabetic Macular Edema: The RESTORE Extension 
Study. Ophthalmology 2014 
Stellungnahme der Deutschen Ophthalmologischen Gesellschaft, der Retinologischen 
Gesellschaft und des Berufsverbandes der Augenärzte Deutschlands (2013) [Available at 
http://cms.augeninfo.de/fileadmin/stellungnahmen/Stellungnahme_DMOE_2014_04.pdf 
(accessed on 28th July 2014)] 
Tong Z, Yang Z, Patel S, Chen H, et al (2008) Promoter polymorphism of the erythropoietin 
gene in severe diabetic eye and kidney complications. Proc. Natl. Acad. Sci. U. S. A 105, 
6998-7003 
Vinores SA, Youssri AI, Luna JD, et al. (1997). Upregulation of vascular endothelial growth 
factor in ischemic and non-ischemic human and experimental retinal disease. Histol 
Histopathol, vol. 12 (1), p.99-109 


Novartis 
Confidential 
Page 59 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
 
13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
Table A1-1 
Critical values for vital signs 
Variable  
Type of abnormality 
Critical values 
Systolic blood pressure 
(mmHg) 
High 
Either >180 with an increase from 
baseline > 30 or > 200 absolute 
Low 
Either < 90 with a decrease from 
baseline > 30 or < 75 absolute 
Diastolic blood pressure 
(mmHg) 
High 
Either >105 with an increase from 
baseline > 20 or > 115 absolute 
Low 
Either < 50 with a decrease from 
baseline > 20 or < 40 absolute 
Pulse rate (bpm) 
High 
Either > 120 with an increase from 
baseline > 25 or > 130 absolute 
Low 
Either < 50 with a decrease from 
baseline > 30 or < 40 absolute 
Table A1-2 
Critical values for laboratory values 
Variable  
Type of abnormality 
Critical values 
Cholesterol 
Out of normal range 
(low): female 
2.38 mmol/l; 92 mg/dl 
Out of normal range 
(low): male 
2.12 mmol/l; 82 mg/dl 
Out of normal range 
(high): female 
6.06 mmol/l; 234 mg/dl 
Out of normal range 
(high): male 
4.97 mmol/l; 192 mg/dl 
Pathologic 
value:  
female and male 
6.22 mmol/l; 240 mg/dl 
Extremely pathologic 
value: 
female 
and 
male 
9.07 mmol/l; 350 mg/dl 
HDL-Cholersterol 
Out of normal range 
(low) 
1.04 mmol/l; 40 mg/dl 


Novartis 
Confidential 
Page 60 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
Pathologic value (low)
0.91 mmol/l; 35 mg/dl  
Extremely pathologic 
value (low) 
0.65 mmol/l; 25 mg/dl  
LDL-Cholesterol 
Out of normal range 
(high) 
3.38 mmol/l; 130 mg/dl  
Pathologic 
value 
(high) 
4.94 mmol/l; 190 mg/dl  
 
Extremely pathologic 
value (high) 
6.50 mmol/l; 250 mg/dl 
Triglycerides 
Out of normal range 
(high) 
1.71 mmol/l; 150 mg/dl  
Pathologic 
value 
(high) 
3.42 mmol/l; 300 mg/dl  
Extremely pathologic 
value (high) 
5.13 mmol/l; 450 mg/dl 
HbA1c 
Out of normal range 
(high) 
6.2% 
Pathologic 
value 
(high) 
6.8% 
Extremely pathologic 
value (high) 
14.6% (deviation alert above 12.1) 


Novartis 
Confidential 
Page 61 
Clinical Trial Protocol (Version No. 01) 
 
Protocol No. CRFB002DDE26 
 
 
 
14 
Appendix 2: PRP (panretinal laser photocoagulation) 
procedures  
PRP should be applied in accordance with DRS recommendations that are as follows: 
• PRP is applied in a scattered pattern to the retina with more than 2 disc diameters from the 
fovea out to the equator and where necessary out to the periphery. 
• The laser spots size in the retina should be 500 microns and the spots 1 burn apart. 1200 to 
1600 burns with mild to moderate intensity are recommended and the burn duration 
should be between 0.1 and 0.2 seconds. If more lasers spots are necessary for sufficient 
initial treatment, further spots can be applied.   
• Usually the treatment is split into 2 to 5 or more sessions within 3 to 6 weeks maximum 
• One session should not exceed 500-600 burns and max. 2 sessions should be made per 
week. 
• If further PRP retreatment is necessary it should not be applied before 3 months have 
passed since last PRP treatment. If investigator is of the opinion that PRP treatment was 
insufficient, PRP treatment should start immediately independent of 3 months interval to 
last laser treatment. 
• About 500 burns are recommended for re-treatment 
To ensure adequate PRP treatment the following recommendations should be taken into 
consideration:   
• sufficient treatment of non-perfused areas 
• laser towards NVEs and eventually also centrally  
• also consider treating NVEs with 100-200µm laser spots that are applied confluent 
 
 

SAP_001.pdf: 
   Clinical Development
RFB002/Ranibizumab/Lucentis®
CRFB002DDE26 / NCT02366468
A 12-months, randomized, VA-assessor blinded, multicenter, 
controlled phase IV trial to investigate noninferiority of two 
treatment algorithms (discretion of the investigator vs. pro re 
nata) of 0.5 mg ranibizumab in patients with visual impairment 
due to diabetic macula edema
Statistical Analysis Plan (SAP) Addendum
Author:
 
Document type:
RAP Documentation: SAP Addendum
Document status:
Final
Release date:
13-Feb-18
Number of pages:
57
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP Addendum
CRFB002DDE26
Table of contents
Table of contents .................................................................................................................2
List of abbreviations............................................................................................................4
Introduction .........................................................................................................................6
Study design.............................................................................................................6
Study objectives and endpoints ...............................................................................7
Statistical methods...............................................................................................................8
Data analysis general information ...........................................................................8
General definitions..................................................................................9
Analysis sets ..........................................................................................................13
Subgroup of interest ..............................................................................14
Visit windowing.....................................................................................................15
Visits .....................................................................................................15
Unscheduled visits ................................................................................15
Patient disposition, demographics and other baseline characteristics ...................16
Patient disposition.................................................................................16
Protocol deviations................................................................................16
Background and demographic characteristics.......................................17
Medical history......................................................................................21
Treatments (study treatment, concomitant therapies, compliance) .......................22
Study treatment/ compliance.................................................................22
Prior and concomitant therapies............................................................25
Analysis of the primary objective..........................................................................26
Primary endpoint...................................................................................26
Statistical hypothesis, model, and method of analysis..........................27
Handling of missing values/censoring/discontinuations.......................28
Supportive analyses...............................................................................28
Analysis of the key secondary objective ...............................................................30
Analysis of secondary efficacy objectives.............................................................30
Secondary endpoints .............................................................................31
Statistical hypothesis, model, and method of analysis..........................31
Handling of missing values/censoring/discontinuations.......................33
33
Safety analyses.......................................................................................................33
Adverse events ......................................................................................33
Intraocular pressure...............................................................................35


Novartis
For business use only
Page 3
SAP Addendum
CRFB002DDE26
Vital signs..............................................................................................35
Laboratory evaluation ...........................................................................36
Pharmacokinetic endpoints....................................................................................37
PD and PK/PD analyses.........................................................................................37
Patient-reported outcomes .....................................................................................37
Biomarkers.............................................................................................................37
37
Interim analysis......................................................................................................42
Sample size calculation .....................................................................................................42
Change to protocol specified analyses ..............................................................................43
Appendix ...........................................................................................................................43
Imputation rules.....................................................................................................43
Adverse Events date imputation............................................................43
Concomitant medication date imputation .............................................45
Medical history date of diagnosis imputation .......................................46
.............................................................46
Efficacy variables and populations for analysis ....................................................47
SAS code for analysis ...........................................................................48
Rule of exclusion criteria of analysis sets..............................................................53
Reference...........................................................................................................................57


Novartis
For business use only
Page 4
SAP Addendum
CRFB002DDE26
List of abbreviations
AE
Adverse Event
AIC
Akaike Information Criteria
ANCOVA
Analyses of Covariance
BCVA
Best Corrected Visual Acuity 
BDRM
Blind Data Review Meeting
BMI
Body Mass Index
CF
Color Fundus
CFP 
Color Fundus Photography
CI
Confidence Interval
CM
Concomitant Medication
CRC
Central Reading Center
cSLO
Confocal Scanning Laser Ophthalmoscope
CSR
Clinical Study Report
CSRT
Central Subfield Retinal Thickness 
CSRV
Central Subfield Retinal Volume 
DBL
Database Lock
DHP
Data Handling Plan
DI
Discretion of the Investigator
DME
Diabetic Macular Edema
DR
Diabetic Retinopathy
DRP
Data Review Plan
DRS
Diabetic Retinopathy Scale
DTS
Data Transfer Specification
eCRF
electronic Case Report/Record Form
ELM
External Limiting Membrane
EoS
End of Study
EoT
End of Treatment
ETDRS
Early Treatment of Diabetic Retinopathy Study
FAS
Full Analysis Set
FCP
Foveal Center Point 
FPFV
First patient first visit
HbA1c
Glycosylated Hemoglobin
IOP
Intraocular Pressure
IRC
Intraretinal Fluid of Cystoid
IRF
Intraretinal Fluid
IVT
Intravitreal
KM
Kaplan-Meier
LOCF
Last Observation Carried Forward 
LPLV
Last patient last visit
LS
Least Square


Novartis
For business use only
Page 5
SAP Addendum
CRFB002DDE26
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed Model Repeated Measurement
NPDR
Non-Proliferative Diabetic Retinopathy
NEI
National Eye Institute
OCT
Optical Coherence Tomography
PD
Protocol Deviation
PDR
Proliferative Diabetic Retinopathy
PED
Pigment Epithelium Detachment
PLS
Product Lifecycle Services
PK
Pharmacokinetics
PRN
Pro re nata
PRP
Panretinal Photocoagulation
PPS
Per Protocol Set
PT
Preferred Term
RMP
Risk Management Plan
RPE
Retinal Pigment Epithelium
RS
Randomized Set
SAE
Serious AE
SAP
Statistical Analysis Plan
SD
Standard Deviation
SD-OCT
Spectral Domain OCT
SF
Subretinal fluid
SI
Standard International 
SOC
System Organ Class
TEAE
Treatment Emergent AE
TFI
Treatment Free Interval
TFLs
Tables, Figures, Listings
VA
Visual Acuity
VI
Visual Impairment
WHO
World Health Organization


Novartis
For business use only
Page 6
SAP Addendum
CRFB002DDE26
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analysis according to Section 9 of 
the study protocol (version no. 1 including Amendment 1) along with any additional analyses, 
specifications or deviations from this protocol planned before unmasking of the data. 
Determination of sample size is specified in Section 3.
This document is written in the future tense. It will be reviewed and updated (including 
conversion to past tense) for entry into the clinical study report (CSR) after the analysis has 
taken place.
Study design
This is a 12-months, phase IV, randomized, parallel-group, visual acuity (VA) 
assessor-masked, multi-center, interventional study to assess the efficacy and safety of 
Discretion of the investigator (DI) vs. Pro re nata (PRN) (as needed) regimens of 0.5 mg 
ranibizumab intravitreal (IVT) injections for adult patients with Type I or Type II diabetes 
mellitus and visual impairment (VI) due to diabetic macular edema (DME). 
A total of 300 patients from approximately 45 centers across Germany were initially planned 
to be randomized and assigned into one of the treatment arms in a ratio of 1:1. After new and 
relevant scientific evidence regarding treatment patterns with ranibizumab was published,
recruitment to the study was revised and reduced to a total of 135 patients randomized and 
assigned in a 1:1 ratio to the treatment arms:

Arm 1 (discretion of the investigator, DI): Investigational, RFB002, 10 mg/ml

Arm 2 (pro re nata, PRN): Standard of Care, RFB002, 10 mg/ml 
The study duration will be up to 13 months (the period of one month is considered to be equal 
30 days):

Screening period: to occur between day -28 and day -3

Baseline period: to occur between day -2 and day 1 

Treatment period: from baseline (visit 2) to month 11

Follow-up period: from month 11 to month 12
For patients randomized to the PRN treatment arm the treatment period is from baseline (date 
of first administration of study treatment) to month 11 with follow-up period up to month 12, 
whereas for patients randomized to the DI treatment arm the treatment period end date 
depends on the patient’s individual schedule which may occur at the month 11 visit, but not 
later.
For patients with last injection at the month 11 visit, the follow-up period ends at the month 
12 visit; for patients with last injection on or before the month 10.5 visit, the follow-up period 
ends on or before the month 11.5 visit.
No interim analyses will be performed.


Novartis
For business use only
Page 7
SAP Addendum
CRFB002DDE26
Figure 1-1
Study design
In this study, the VA assessor, who is assessing parameters constituting the primary endpoint 
(best corrected visual acuity [BCVA]), will be masked to the treatment regimen and will not 
be allowed to perform any additional study tasks which would unmask him/ her to study 
treatment.
 
 
Any personnel involved with the statistical analysis and interpretation of the data and results 
will be masked until Database Lock (DBL).
Following protocol amendment 1, patient recruitment was revised and reduced. Therefore the 
original assumed patient number for primary outcome (mean average BCVA change from 
baseline to month 12) will not be reached; hence all data analysis of this study will be purely 
exploratory.
Study objectives and endpoints
The primary objective of this trial is to demonstrate that the mean average change from 
baseline of BCVA in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters 
averaged over all post-baseline visits to month 12 in patients with DME treated with 
ranibizumab injections at the DI and in accordance with disease activity criteria is non-
inferior to current standard of care (PRN).
The secondary objectives seek to evaluate:

Mean change of BCVA in ETDRS letters from baseline to month 12

Frequency of visits, injections and treatment free intervals (TFIs)

Mean change of central subfield retinal thickness (CSRT) and foveal center point
(FCP) thickness from baseline to month 12

Change in Diabetic Retinopathy Scale (DRS) from baseline to month 12

Influence of relevant glycosylated hemoglobin (HbA1c), blood pressure, and blood 
lipid levels changes on the primary objective
:


Novartis
For business use only
Page 8
SAP Addendum
CRFB002DDE26
Statistical methods
Data analysis general information
The analysis will be performed by Novartis Product Lifecycle Services (PLS). SAS® Version 
9.4 or higher will be used for generating tables, figures, and listings (TFLs).
Data will be summarized for all patients with respect to background, demographic and 
baseline characteristics, efficacy and safety observations and measurements. 
Descriptive statistics (the number of non-missing observations [n], mean, median, standard 
deviation [SD], lower quartile [Q1], upper quartile [Q3], minimum, and maximum values) 
will be presented for continuous variables. The following number of decimal places will be 
used: mean, median, Q1, and Q3 values to 1 more decimal place than the raw data; minimum 
and maximum to the same number of decimal places as the raw data and SD to 2 more 
decimal places than the raw data. 


Novartis
For business use only
Page 9
SAP Addendum
CRFB002DDE26
For categorical variables, the number and percentage of each category within a variable will 
be calculated. If a count of zero is obtained for categorical data, only the zero count (no 
percentage) will be displayed. If no treatment arm satisfies a category, then the category will 
be displayed, with the exception of the protocol deviations (PDs) summary. A row (category) 
denoted “Missing” will be included in count tabulations if a non-zero count of missing values 
is present for any of the treatment arms. In addition, the corresponding percentage for this row 
will be displayed.
The study eye is the eye selected by the investigator at baseline (according to the protocol) to 
receive the study treatment. The fellow eye is the non-study eye.
For non-ocular, study eye, fellow eye and both eyes summary TFLs will be based on all 
patients included in the analysis population under consideration. 
Assessments documented in the database as occurring in “both eyes” will be summarized and 
listed for both eyes in addition to each eye separately. To facilitate derivations and analysis 
based on study eye and fellow eye database records for “both eyes” will be split to two 
records containing identical information as the original record with the exception of the site 
which shall be recoded to “Right” and “Left”, respectively.
The type of retinal disease and the optical coherence tomography (OCT) device used to 
analyse retinal thickness assessments can lead to variation in results (Han IC and Jaffe GJ 
2009, Mylonas et al 2009). Therefore an adjustment to the affected variables will be made, 
details are provided in Section 2.1.1. The adjusted affected variables will be used for all TFLs, 
unless stated otherwise.
As the original assumed patient number for the primary outcome will not be reached, the data 
analysis will be purely exploratory. Nevertheless, statistical testing will still be performed, as 
stated in the protocol.
All data will be listed by patient, unless stated otherwise.
General definitions
The investigational treatment is 0.5 mg ranibizumab 10 mg/ml solution for injection, taken by 
patients in two different regimes: PRN or DI.
In this study, PRN is defined as the regime where after initial monthly therapy until maximum 
BCVA and no signs or no further improvement of disease activity, patients are monitored 
every month and retreated if any signs of disease activity occur.
DI is defined as the regime where the investigator treats patients at own discretion after initial 
monthly treatment until maximum BCVA and no signs or no further change of disease 
activity.
The study treatment period will be defined as starting from baseline (visit 2), which is the date 
of first administration of study treatment, until the last treatment (laser photocoagulation and/ 
or ranibizumab) prior to the patient's month 12 (follow-up) visit, which is called the date of 
last administration of study treatment.
There are two separate treatment phases within the study period:


Novartis
For business use only
Page 10
SAP Addendum
CRFB002DDE26

an initial treatment phase
This is the period from first administration of study treatment in the study eye until the 
first NO treatment given based on the Ranibizumab dose administration electronic 
Case Report/Record Form (eCRF) when the reason for NO treatment given is one of 
the following three stability criteria:

No disease activity (BCVA maximum, CRT minimum and no further signs of 
activity in morphologic parameters)

Disease activity stable with maximum BCVA (no further improvement of other 
morphologic parameters)

BCVA and disease activity stable (no further improvement of BCVA and other 
morphologic parameters).
Note: If the reason for NO treatment given was either:

Adverse event

Disease activity present but patient refused additional treatment
the patient will continue to remain in the initial treatment phase until the reason for 
NO treatment given is one of the aforementioned three stability criteria.

a maintenance phase
This is the period from after the end of the initial treatment phase (first NO treatment 
given based on the Ranibizumab dose administration eCRF) until End of Study (EoS) 
visit.
The study day for a baseline or post-baseline scheduled or unscheduled visit is defined as

Study day = (Date of visit) – (Date of baseline visit) + 1
Baseline is the date of first administration of study treatment in the study eye. If a patient is 
randomized but not treated then the baseline is defined as the date of randomization. Baseline 
value will be considered as the value of the last assessment collected prior to start of treatment 
(i.e. data from screening or baseline). 
The final contact with patients will be during the 30 days either:

following the last study visit, or

following the last administration of study treatment (laser photocoagulation and/ or 
ranibizumab) if there are post-treatment follow-up visits (whichever is later), including 
a final contact at the 30-day point.
A re-treatment during the maintenance phase is defined as an administration of study 
treatment (active ranibizumab) (YES treatment given) following at least one NO treatment 
given based on the Ranibizumab dose administration eCRF when the reason for NO treatment 
given is one of the three stability criteria. A patient may have multiple re-treatments.
A TFI is the interval between the first NO treatment given when the reason for NO treatment 
given is one of the three stability criteria and the first subsequent YES treatment given after 
that. This will be based on the Ranibizumab dose administration eCRF. A patient may have 
multiple TFIs.


Novartis
For business use only
Page 11
SAP Addendum
CRFB002DDE26
Note: If a patient had no treatment at month 2, missed month 3 and received treatment at 
month 4 then we can assume that the duration of each month is 30 days; hence this interval 
would be 30 + 1 days.
Stability was to be judged by the investigators during the trial. However, to assess compliance 
with objective stability criteria, the following definitions are introduced:
a) BCVA will not be regarded as stable if there is a change in BCVA of >= 5 letters 
compared to the previous visit.


Novartis
For business use only
Page 12
SAP Addendum
CRFB002DDE26
b) Retinal thickness (disease activity) will not be regarded as stable if there is a change
of >=10% in uncorrected CSRT compared to the previous visit.
Stability compliance assessment will be based on the presence of fluid, BCVA stability, and 
retinal thickness stability. This will be derived during the maintenance phase when NO 
treatment given is recorded on the Ranibizumab dose administration eCRF when the reason 
for NO treatment given is one of the following three stability criteria:

No disease activity (BCVA maximum, CRT minimum and no further signs of activity 
in morphologic parameters)

Disease activity stable with maximum BCVA (no further improvement of other 
morphologic parameters)

BCVA and disease activity stable (no further improvement of BCVA and other 
morphologic parameters).
It will be categorized as follows:
1. No presence of fluid and BCVA stable and retinal thickness stable
2. No presence of fluid and BCVA stable and retinal thickness not stable
3. No presence of fluid and BCVA not stable and retinal thickness stable
4. No presence of fluid and BCVA not stable and retinal thickness not stable
5. Presence of fluid and BCVA stable and retinal thickness stable
6. Presence of fluid and BCVA stable and retinal thickness not stable
7. Presence of fluid and BCVA not stable and retinal thickness stable
8. Presence of fluid and BCVA not stable and retinal thickness not stable
Patients treated not in line with the stability compliance assessment will be deemed as those 
who according to the definition of the study compliance assessment did not meet the stability 
criteria but still had a NO treatment given record on the Ranibizumab dose administration 
eCRF when the reason for NO treatment given is one of the three stability criteria at the same 
visit. Otherwise they will be regarded as treated in line with the stability compliance 
assessment.
The stability compliance assessment will be further categorized as:

Full stability (Yes, No)

Yes refers to “No presence of fluid and BCVA stable and retinal thickness stable”
(criterion 1 mentioned above)

No refers to any of the other categories (criteria 2 to 8 mentioned above)

Overall full stability (Yes, No)

Yes refers to when for each occurrence of NO treatment given due to one of the 
aforementioned three stability criteria for a patient the stability compliance 
assessment is always “No presence of fluid and BCVA stable and retinal thickness 
stable” (criterion 1 mentioned above)

No refers to when for each occurrence of NO treatment given due to one of the 
aforementioned three stability criteria for a patient at least once the stability 


Novartis
For business use only
Page 13
SAP Addendum
CRFB002DDE26
compliance assessment is not “No presence of fluid and BCVA stable and retinal 
thickness stable” (criterion 1 mentioned above)
The following OCT variables: CSRT, FCP thickness will be adjusted based on the OCT 
device used according to the correction factors outlined in Table 2-1.
Table 2-1
OCT correction factors
Variables
OCT device
Correction factor
CSRT (µm)
Heidelberg Spectralis               No correction required
Cirrus Zeiss*                             Add 56,29 µm to unadjusted value
Topcon
Add 121,72 µm to unadjusted value
Other **
No correction required
NA **
No correction required
FCP thickness (µm)
Heidelberg Spectralis               No correction required
Cirrus Zeiss*                             Add 28,3 µm to unadjusted value
Topcon
No correction required
Other **
No correction required
NA **
No correction required
* The Cirrus Zeiss OCT device refers to Cirrus Zeiss Macular Cube 512 x 128 x 1024.
** A correction factor is not applicable in this case.
Analysis sets
The Randomized Set (RS) will consist of all patients who were randomized to one of the 
treatment arms and who received at least one application of study treatment.
The Full Analysis Set (FAS) will consist of all patients as randomized who received at least 
one application of study treatment and have at least one post-baseline assessment for the 
primary endpoint (BCVA). Following the intent-to-treat principle, patients will be analyzed 
according to the treatment assigned. No data will be excluded from the FAS analyses because 
of PDs.
The Per Protocol Set (PPS) will consist of all patients in the FAS who received study 
treatment as randomized and completed the treatment phase of the trial without major PDs.
Criteria that are assumed to impact the PPS will be defined in the data review plan (DRP), 
data handling plan (DHP), and Blind Data Review Meeting (BDRM) before DBL.
The Safety Set will consist of all patients from the RS who had at least one post-baseline 
safety assessment. Patients will be analyzed according to treatment received. The statement 
that a patient had no AEs also constitutes a safety assessment.
For rules of exclusion criteria of analysis sets refer to Appendix 5.3.


Novartis
For business use only
Page 14
SAP Addendum
CRFB002DDE26
Table 2-2
Analysis data sets for specific outputs
All screened 
patients
RS
FAS
PPS
Safety 
Set
Screening failures
X
Demographics and baseline 
characteristics
X
Analysis sets
X
Patient disposition
X
X
Number of patients by visit
X
Protocol deviations
X
Medical history
X
Concomitant medication
X
Primary and key secondary 
efficacy variables
X
X
Other efficacy analyses
X
Patient reported outcomes
X
Safety analyses
X
Exposure
X
Subgroup analyses
X
Non-inferiority analyses
X
X
The number and percentage of patients in each analysis set will be summarized based on the 
RS.  
Subgroup of interest
Gender subgroup analysis will be done for the primary objective.
For patients with 
, for patients that needed additional 
panretinal photocoagulation (PRP) treatment and for patients experiencing an incident leading 
to vitrectomy (see Section 2.1.1 for definition of the subgroups of interest), separate subgroup 
analysis will be presented using the endpoints:

BCVA changes in ETDRS letters from baseline to month 12

Number of visits and treatments

Progression/ regression of neovascularization from baseline to month 12 (i.e. change 
in PDR in the study eye from baseline to month 12)

Changes in CSRT from baseline to month 12 at each visit
Patients with missing baseline values used to define the subgroups will be presented in a 
category “unknown” in the respective subgroup analyses.


Novartis
For business use only
Page 15
SAP Addendum
CRFB002DDE26
Visit windowing
Visits
Visit windowing will be performed for all post-baseline visits collected in the database where 
the patients have more than one post-baseline visit assessment which will be summarized by 
visit. The screening and baseline visits will not be remapped. The study day for each visit will 
be derived (see Section 2.1.1 for definition); this day will be then be used to determine the 
actual visit based on the visit windows outlined in Table 2-3.
As it is planned to have both end of treatment (EoT) and EoS analyses for certain assessments, 
respective flags will be created for the assessments of interest. The EoT flag will flag all 
values which occur up and including EoT while the EoS flag will flag all values collected. If 
more than one remapped visit occurs at a visit, only one will be selected for summary tables 
but all visits will be listed. Therefore two additional variables will be created which will 
indicate which values will be used for analysis purposes for EoT and EoS analyses 
respectively. If more than one remapped post-baseline value for the respective analyses occurs 
at a visit, only the value closest to the target study day will be selected (see Section 2.1.1 for 
definition). If there are two observations which have the same difference in days to the target 
day or if there are two observations on the same day, the first value will be used. 
Table 2-3
Visit windows (monthly) 
Post-baseline timepoint
Visit timepoint 
(monthly)
Target Study day
Visit window
(study days)
3
Month 1
30
2 to 44
4
Month 2
60
45 to 74
5
Month 3
90
75 to 104
6
Month 4
120
105 to 134
7
Month 5
150
135 to 164
8
Month 6
180
165 to 194
9
Month 7
210
195 to 224
10
Month 8
240
225 to 254
11
Month 9
270
255 to 284
12
Month 10
300
285 to 314
13
Month 11
330
315 to 344
14
Month 12
360
>=345
Unscheduled visits
All data collected at unscheduled visits will at a minimum be listed.
All safety and exposure to study treatment data collected at unscheduled visits will be used.


Novartis
For business use only
Page 16
SAP Addendum
CRFB002DDE26
Patient 
disposition, 
demographics
and 
other 
baseline 
characteristics
Demographics, baseline ocular and non-ocular characteristics will be summarized and listed 
for the FAS for each randomized treatment arm and overall, unless specified otherwise. 
No inferential statistical analysis will be performed on these characteristics. 
Patient disposition
The number and percentage of patients who are screening failures and the reason for 
screening failure will be presented for all patients screened. 
Patient disposition will be summarized for all patients by treatment arm and overall. The 
number and percentage of patients who completed the study, who discontinued the study early, 
and also who prematurely discontinued treatment but remained in the study will be displayed. 
For those who discontinued the study early or who discontinued the investigational study 
treatment prematurely but remained in the study, the primary reason for study or 
investigational study treatment discontinuation will be summarized. 
Study completion and investigational study treatment completion will also be summarized by 
the visit of study termination/ completion and study treatment discontinuation/ completion, 
respectively. 
The number and percentage of patients attending each visit will also be presented by treatment
arm.
Furthermore, disposition will be presented in by-patient listings. A study milestones listing 
will also be provided containing first patient first visit (FPFV), last patient last visit (LPLV) 
and the trial duration (the time period between FPFV and LPLV), overall and by site. 
Protocol deviations
PD severity and impact on analysis populations can be found in the DRP and DHP, these are 
subject to change however and the final definitions and list of PDs will be documented during 
the BDRM. The PDs are used in excluding entire patients or particular data within a patient 
from relevant analysis sets. Criteria defining PDs are outlined in the Appendix 5.3.
All PDs will be summarized through presenting the number and percentage of patients with 
each deviation by treatment arm and total.
Patients with multiple PDs will only be counted once at each level of summarization. 
Additionally all relevant (according to medical review) reportable protocol deviations will be 
summarized under the following deviation categories used in the DRP and DHP. Currently 
these are:

Patient did not satisfy relevant inclusion criteria (I)

Patient met relevant exclusion criteria (E)

Patient received the wrong treatment or incorrect dose (S)

Patient developed withdrawal criteria during the study, but not withdrawn (D)


Novartis
For business use only
Page 17
SAP Addendum
CRFB002DDE26

Patient took an excluded concomitant medication (M)

Others (O)
In addition, a listing of PDs will be produced including the date and study day of the deviation 
occurrence with the accompanying deviation code and severity. 
Background and demographic characteristics
Demographics and baseline data will be summarized and listed for the FAS by treatment arm
and overall, unless specified otherwise. Descriptive statistics will be provided for the below 
demographics and baseline characteristics:
Demographics
Continuous variables:

Age (years)
Categorical variables:

Age group (<65, >=65 years)

Sex (Male, Female)

Race (Caucasian, Black, Asian, Other)
Non-ocular baseline characteristics
Continuous variables:

Vital signs (height [cm], weight [kg], pulse [bpm], systolic and diastolic blood 
pressure [mmHg])

Body mass index (BMI) (kg/m2) 

HbA1c (%)

Serum Lipid Levels (Cholesterol, HDL-Cholesterol, LDL-Cholesterol, Triglycerides) 
(mg/dL) 

Estimated number of cigarette pack years

Time since smoking termination (years)

Note: Time since smoking termination is only completed for ex-smokers.

Time since first diagnosis of diabetes (years)
Categorical variables:

Pregnancy testing for women of child-bearing potential (Negative, Positive)

Smoking history (Never smoked, Current smoker, Ex-smoker)

Time since smoking termination group (< 2, 2 to < 10, 10 to < 20, >= 20 years)

Note: Time since smoking termination is only completed for ex-smokers.

Diabetes type (Type I, Type II)


Novartis
For business use only
Page 18
SAP Addendum
CRFB002DDE26

Time since first diagnosis of diabetes group (< 2, 2 to < 10, 10 to < 15, 15 to < 20, >= 
20 years)
Ocular baseline characteristics
Continuous variables:

Time since first diagnosis of DME (years) (study eye, fellow eye)

BCVA (letters) (study eye, fellow eye)

Intraocular pressure (mmHg) (study eye, fellow eye)
Categorical variables:

Time since first diagnosis of DME group (< 2, 2 to < 10, 10 to < 15, 15 to < 20, >= 20 
years) (study eye, fellow eye)

Study eye selection (Left, Right) (study eye)
 
The following assessments presenting retinal characteristics are provided by the CRC.
OCT baseline characteristics (from CRC)
Continuous variables:

CSRT (µm) (study eye)


FCP thickness (µm) (study eye)




Categorical variables:







Novartis
For business use only
Page 19
SAP Addendum
CRFB002DDE26

Automated segmentation of CSRT (Correct, Error manually corrected, Manual 
correction too time-consuming, Not gradable, NA) (study eye)


CSRT >=300 µm (Yes, No, Not gradable, NA) (study eye)










Automated or manually corrected segmentation of CSRT by OCT software (Correct, 
Manually measured, Not gradable, NA) (study eye)

Note: The descriptive statistics summary table and listing for OCT baseline characteristics 
will also be produced using the unadjusted CSRT and FCP thickness values.
Color Fundus Photography (CFP) baseline characteristics (from CRC)
The following variables will only be listed by treatment arm.
Categorical variables:

CFP modality available? (Yes - Required; Yes - Not required; No – Required; No -
Not required) 

CFP quality OD (Excellent, Good, Adequate, Poor, NA)

CFP quality OS (Excellent, Good, Adequate, Poor, NA)

CFP submission acceptance (Completely acceptable, Acceptable with remarks, Not 
acceptable, NA)


Novartis
For business use only
Page 20
SAP Addendum
CRFB002DDE26
DRS baseline characteristics (from CRC)
Categorical variables:

DRS 
(Mild*NPDR,
Moderate*NPDR,
Severe*NPDR,
Proliferative 
Diabetic 
Retinopathy, Status post panretinal laser coagulation - not gradable, NA) (study eye, 
fellow eye)
General image grading characteristics (from CRC)
Categorical variables:

Confirmed eligibility of study eye (Yes, No, NA)

Concerns for fellow eye to be considered as study eye alternatively at screening (Yes, 
No, NA)

Adequacy of image quality for eligibility (Yes, No, Questionable, Not gradable, NA) 

Presence of any diabetic macular edema (Yes, No, Questionable, Not gradable, NA) 
(study eye)

No presence of concomitant conditions that would prevent improvement (Yes, No, 
Questionable, Not gradable, NA) (study eye)

No presence of structural damage in the center of the macula (Yes, No, Questionable, 
Not gradable, NA) (study eye)

No presence of vitreous hemorrhage impairing the adequate diagnosis (Yes, No, 
Questionable, Not gradable, NA) (study eye)

No presence of relevant vitreofoveal adhesion or epiretinal membrane with foveal 
involvement (Yes, No, Questionable, Not gradable, NA) (study eye)

No presence of proliferative vitreoretinopathy (Yes, No, Questionable, Not gradable, 
NA) (study eye)

No presence of central retinal neovascularizations (Yes, No, Questionable, Not 
gradable, NA) (study eye)

Presence of signs of vitreous hemorrhage (Yes, No, Questionable, Not gradable, NA) 
(study eye, fellow eye)


Novartis
For business use only
Page 21
SAP Addendum
CRFB002DDE26

Presence of signs of panretinal laser coagulation (Yes, No, Questionable, Not gradable,
NA) (study eye, fellow eye)

Presence of signs of laser treatment of the macula (Yes, No, Questionable, Not 
gradable, NA) (study eye, fellow eye)

Lens status (Phakic, no marked opacity; Phakic, marked opacities; Pseudophakic; 
Aphakic; Other; Not gradable; NA) (study eye, fellow eye)

Capillary non-perfusion – general (Yes, No, Questionable, Not gradable, NA) (study 
eye, fellow eye)

Capillary non-perfusion – involvement of center (Yes, No, Questionable, Not gradable, 
NA) (study eye, fellow eye)

Capillary non-perfusion – area extent (≤ 3 PD, > 3 PD ≤ 5 PD, > 5 PD ≤ 7 PD, > 7 PD 
≤ 10 PD, > 10 PD, NA) (study eye, fellow eye)
The following ocular assessments (confocal scanning laser ophthalmoscope [cSLO]) are 
optional. They will only be performed for patients with the respective additional informed 
consent in participating centers equipped with the respective device.
cSLO baseline characteristics (from CRC)
Categorical variables:

cSLO modality available? (Yes - Required; Yes - Not required; No – Required; No -
Not required) 

IR image quality (Excellent, Good, Adequate, Poor, NA)

Multicolor quality (Excellent, Good, Adequate, Poor, NA)

FAF quality (Excellent, Good, Adequate, Poor, NA)

cSLO submission acceptance (Completely acceptable, Acceptable with remarks, Not 
acceptable; NA)
 
 
 
Medical history
The number and percentage of patients from the FAS with relevant medical history (ocular 
and non-ocular) and current medical conditions will be tabulated by system organ class (SOC) 
and PT of the current Medical Dictionary for Regulatory Activities (MedDRA) dictionary
(version 19.1 or higher). The SOCs will be presented in alphabetical order. PTs will be 
ordered by treatment arm and total by decreasing proportion in the total group.
Separate summaries will be presented for histories and current medical conditions 
(documented in the database as still active at the start of the study). Additionally, these tables 


Novartis
For business use only
Page 22
SAP Addendum
CRFB002DDE26
will be provided separately for ocular (presented for both eyes in addition to study eye and 
fellow eye separately) and non-ocular histories and conditions. 
For handling of missing or incomplete start and end dates, see Appendix 5.1.3 of this 
document.
Additionally all information will be listed including the investigator reported term and the 
diagnosis/ surgery date and day.
Treatments (study treatment, concomitant therapies, compliance)
Summaries will be presented for the Safety Set. All analyses will be presented for the study 
eye only, unless specified otherwise.
The fellow eye is not treated with investigational study treatment and will therefore not be 
applicable for Section 2.5.1.
Study treatment/ compliance
2.5.1.1
Investigational treatment
Descriptive statistics for the total number of ranibizumab injections will be presented for each 
treatment phase separately and overall by treatment group and total. Summary statistics for 
the number of injections per patient will be presented by frequency distribution (number of 
patients with 1 injection, number of patients with 2 injections, on up to the maximum number 
of injections for any one patient) for the given treatment phase and overall, and cumulatively.
Descriptive statistics will also be provided by treatment arm and total for:

duration of the overall study period

duration of the initial treatment phase 

duration of the maintenance phase

duration of time between visits (overall and for maintenance phase) 

duration of time between injections (overall and for maintenance phase) 
This table will also be repeated by actual treatment strategy. Furthermore, duration of time 
between visits and duration of time between injections will be presented overall and by actual 
treatment strategy from month 4 onwards
At each visit, the number and percentage of patients receiving or not receiving a ranibizumab 
injection will be summarized from baseline to month 11. Additionally, the reasons for no 
study treatment given will be summarized. This will include details for disease activity as 
recorded in the Ranibizumab dose administration eCRF (no disease activity, disease activity 
stable with maximum BCVA, BCVA and disease activity stable, Adverse event or disease 
activity present but patient refused additional study treatment). The denominator at each visit 
will be the number of patients for which a study treatment decision was recorded in the eCRF 
at that visit.
A frequency table will be presented at each visit showing the number and percentage of 
patients for overall and each individual stability compliance assessment category (see Section 
2.1.1 for definition of the stability compliance assessment) who stopped treatment due to one 
of the following three stability criteria:


Novartis
For business use only
Page 23
SAP Addendum
CRFB002DDE26

No disease activity (BCVA maximum, CRT minimum and no further signs of activity 
in morphologic parameters)

Disease activity stable with maximum BCVA (no further improvement of other 
morphologic parameters)

BCVA and disease activity stable (no further improvement of BCVA and other 
morphologic parameters).
By-patient listings for ranibizumab injection administration will be provided.
Descriptive statistics presenting the total number of cases (patient and event counts) where 
patients were treated not in line with the stability compliance assessment (see Section 2.1.1
for definition of such patients) and the frequency distribution (number of patients treated in 
line with the stability compliance assessment, number of patients treated once not in line with
the stability compliance assessment, number of patients treated twice not in line with the 
stability compliance assessment, on up to the maximum number of cases where patients were 
treated not in line with the stability compliance assessment for any one patient) will be 
presented for the maintenance phase by treatment arm and total. Alignment with the stability 
compliance assessment (Yes, No) will be included in the ranibizumab injection administration 
by-patient listing.
Descriptive statistics will be provided for the duration of:

study observation period (Date of last visit – Date of first administration of study 
treatment + 1 day)

study treatment period (Date of last administration of study treatment – Date of first 
administration of study treatment + 1 day). 
The duration will be categorized into periods of 30 days. Descriptive statistics for the duration 
of study treatment period will also be provided by overall stability compliance assessment 
(refer to Section 2.1.1 for definition).
The number and percentage of patients for whom the visit interval was increased, kept or 
reduced will be summarized by visit. Additionally, the reasons for increasing, reducing, or 
keeping the visit interval the same, as recorded in the Visit Interval eCRF will be listed. This 
listing will be repeated for those patients with a treatment pattern which includes X (see 
Section 2.5.1.1.1 for definition), the listing will also include the visit structure and associated 
visit dates.
The source of confirmation of disease activity as provided in the eCRF (BCVA, OCT, 
Ophthalmoscopy, CFP, FA, Other) will be also be listed.
2.5.1.1.1 Investigational treatment pattern
The pattern of ranibizumab treatment administrations will be summarized for both treatment 
arms from baseline to month 12. For a given patient, the pattern of ranibizumab treatments 
will be identified by a series of numbers or letters as defined below:

T indicates EoT visit (only for patients who discontinue treatment early but stay in the 
study)

S indicates EoS visit 


Novartis
For business use only
Page 24
SAP Addendum
CRFB002DDE26

X indicates an extended interval where no visit was required in the maintenance phase 
for a patient due to DI with an actual treatment strategy of Dynamic PRN or Treat & 
Extend

M indicates that the patient missed the visit

0 indicates that a patient attended the scheduled visit at which study treatment was not 
given

1 indicates that a patient attended the scheduled visit at which study treatment was 
given

F indicates a follow-up visit after EoT without further treatment
For example, if a patient received injections at baseline, months 1 to 5, 8 and 10, attended the 
visit at months 6 and 7 but was not treated in the study eye, missed month 9, discontinued 
prior to month 12, the ranibizumab treatment pattern for that patient would be 111111001M1S.
Investigational treatment patterns will be listed for all patients. 
2.5.1.1.2 Re-treatments
The definition of re-treatment is provided in Section 2.1.1.
Descriptive statistics for the number of ranibizumab re-treatments during the maintenance 
phase and the frequency distribution (number of patients without any re-treatment, number of 
patients with 1 re-treatment, on up to the maximum number of re-treatments for any one 
patient) will be presented by treatment arm and total. Re-treatment will only be derived for 
those patients with a completed initial treatment phase.
The time to first ranibizumab re-treatment (in days) during the maintenance phase will be 
calculated as the period between the date of the first injection (YES treatment given) in the 
maintenance phase and the date of the start of the maintenance phase (NO treatment given
when the reason is one of the three stability criteria, as defined in Section 2.1.1) + 1 day.
Note: If a patient had no treatment at month 3, missed month 4 and received treatment at 
month 5 then we can assume that the duration of each month is 30 days; hence time to re-
treatment would be 30 + 1 days.
Kaplan-Meier (KM) curves and descriptive statistics will be provided for time to re-treatment. 
The main focus of this study is to understand the effect of the two treatments of interest. 
Therefore, time to first re-treatment during the maintenance phase will be derived for:
1. up to EoT 
This means: 

if a patient prematurely discontinues treatment (EoT) but stays in the study longer 
(EoS > EoT), then only data up to EoT will be used for calculation and censoring

if a patient prematurely discontinues treatment and the study at the same time, then 
data up to EoS will be used for calculation and censoring

if a patient does not discontinue treatment early, then data up to EoS will be used
for calculation and censoring


Novartis
For business use only
Page 25
SAP Addendum
CRFB002DDE26
2. up to EoS
In case of no ranibizumab re-treatment, the duration will be censored at EoS.
In addition, time to first re-treatment during the maintenance phase will be derived excluding 
those patients who discontinue treatment early but stay in the study.
The number and percentage of patients experiencing re-treatments during the maintenance 
phase, together with defined reason for re-treatments, will be displayed by visit.
In addition, descriptive statistics for duration of TFI will be provided by treatment arm and 
total. A frequency table for the number of TFIs experienced will also be presented.
The proportion of patients with a TFI during the maintenance phase of at least 3 months will 
be also be summarized by treatment arm and total.
2.5.1.2
Laser Photocoagulation
Different types of laser treatments and regimes can be applied in addition to study treatment 
to the patients in both arms: 

Focal

Grid

Panretinal

Focal + Grid

Panretinal + Focal + Grid           

Other
The number of laser treatments up to month 12 will be presented for both treatment arms by 
frequency distribution (number of patients with no laser treatments, number of patients with 1 
laser treatment, on up to the maximum number of laser treatments for any one patient) and 
cumulatively. Summaries will be presented separately for the different types of laser treatment 
(see Section 2.1.1).
Summary tables with the number and percentage of patients who received laser treatment or 
not and the reason for laser treatment as stated in eCRF will be given by visit.
By-patient listings for laser photocoagulation will be provided.
Prior and concomitant therapies
The number and percentage of patients taking concomitant therapies will be summarized by 
PT according to the WHO Drug Reference List dictionary (version 15.3 or higher). 
Summaries of the following will be presented by treatment arm:

Prior therapies: therapies received prior to the start of study treatment (therapy end 
date prior to date of first administration of any study treatment) 

Concomitant therapies: therapies received on/ after the start of study treatment 
(therapy end date on or after the date of first administration of any study treatment)
Note: Therapies which started prior to the start of study treatment but continued into 
the treatment period will be classified as concomitant.


Novartis
For business use only
Page 26
SAP Addendum
CRFB002DDE26
For both, prior and concomitant therapies, summary tables will be presented for ocular 
therapies (for both eyes in addition to study eye and fellow eye separately) and non-ocular 
therapies. 
Concomitant medications as well as significant non-drug therapies that are prohibited as per 
protocol and given during the conduct of the study while on study treatment will be provided 
in separate tables. These patients will be identified using the PD M06 (see Appendix 5.3 for 
details on this PD) and the prohibited medications and significant non-drug therapies will be 
identified by the medical advisor during the BDRM.
For those patients who discontinued the investigational study treatment prematurely but 
remained in the study, summary tables will be presented for concomitant ocular therapies (for 
both eyes in addition to study eye and fellow eye separately) and non-ocular therapies that 
were received after the EoT visit.
For handling of missing or incomplete start and end dates, see Appendix 5.1.2 of this 
document.
By-patient listings for prior and concomitant therapies will be provided.
Analysis of the primary objective
The primary objective is to demonstrate that the mean average change of BCVA, averaged 
over all post-baseline visits to month 12, in patients with DME treated with ranibizumab 
injections at the discretion of the investigator (DI) and in accordance with disease activity 
criteria is non-inferior to current standard of care (PRN).
The main focus of this study is to understand the effect of the two treatments of interest. 
Therefore, data from baseline to EoT will be used for primary objective analyses, unless 
specified otherwise. This means: 

if a patient prematurely discontinues treatment (EoT) but stays in the study longer 
(EoS is after EoT), then only data up to EoT will be used

if a patient prematurely discontinues treatment and the study at the same time, then 
data up to EoS will be used

if a patient does not discontinue treatment early, then data up to EoS will be used.
In the cases where patients discontinued study treatment early but continued in the study, 
further sensitivity analysis using any BCVA data collected after treatment ended until the 
patient completed the study will be presented as defined in Section 2.6.4.
Only the study eye will be evaluated for efficacy. 
Primary endpoint
The primary efficacy variable of this study is the mean average change from baseline in 
BCVA over the 12-month treatment period. This is defined as the difference between the 
average level of BCVA (ETDRS letters) over all post-baseline assessments from month 1 to 
month 12 (or premature discontinuation if earlier) and the baseline level of BCVA. Average 
change from baseline in BCVA will henceforth be referred to as visit-averaged change from 


Novartis
For business use only
Page 27
SAP Addendum
CRFB002DDE26
baseline in BCVA. Therefore the primary efficacy variable of this study is the mean visit-
averaged change from baseline in BCVA from month 1 to EoT.
That is, if BCVA0, BCVA1, BCVA2, …, and BCVA12 define BCVA measurements at 
baseline, month 1, month 2, …, and month 12, respectively, then the primary efficacy variable 
D0 is derived as:
D0 = [(BCVA1 + BCVA2 + … + BCVA12)/12] – BCVA0
The primary analysis will be performed after all patients have completed the month 12 visit
(or discontinued the study prematurely before month 12) using the FAS based on the Last 
Observation Carried Forward (LOCF). 
Statistical hypothesis, model, and method of analysis
As a consequence of the early recruitment termination, all analyses will be interpreted in a 
purely descriptive manner. Nevertheless, the planned non-inferiority hypothesis testing of the 
ranibizumab injections at the discretion of the investigator (DI) and ranibizumab injections of 
current standard care (PRN) for patients with DME will still be performed.
The following hypotheses related to non-inferiority at a one-sided 0.025 significance level 
will be performed:
Null hypothesis: H0: μDI - μPRN ≤ - Δ 
Alternative hypothesis: HA: μDI - μPRN > - Δ
where μDI and μPRN are the unknown mean visit-averaged change from baseline in BCVA 
from month 1 to EoT, in the DI regimen and the PRN regimen, respectively. Δ is the non-
inferiority margin and is predefined to be 4 letters. The hypothesis testing with respect to non-
inferiority of BCVA will be carried out using an analysis of covariance (ANCOVA) model 
including study treatment (DI, PRN) and center as factors and baseline BCVA as continuous 
covariate.
The Least Square (LS) (“adjusted”) means for each treatment arm and estimates of the 
difference (DI - PRN) will be given along with the respective two-sided, 95% CI and the 
p-value for the (unshifted) null hypothesis (μDI - μPRN = 0). 
The one-sided non-inferiority p-value for the shifted hypothesis (μDI - μPRN ≤ - Δ) will be 
calculated. Non-inferiority will be claimed, if the lower limit of the two-sided 95% CI 
(equivalent to the one-sided 97.5% CI) does not exceed – Δ (i.e. -4 letters).
There are no multiplicity issues as there is only one primary comparison.
The key assumptions that underlie the use of ANCOVA model for the primary analysis will 
be checked. The normality assumption of the error term will be performed and in case of clear 
deviations, a non-parametric comparison – Wilcoxon Rank Sum Test – will be performed 
instead of ANCOVA for the primary analyses. Homogeneity of variance between/ among 
treatment arms will be evaluated visually.
At each visit, descriptive statistics will be provided for the following values of the primary 
efficacy variable BCVA by visits and treatment arms:


Novartis
For business use only
Page 28
SAP Addendum
CRFB002DDE26

Baseline

Absolute and change from baseline 

Visit-averaged change from baseline in BCVA from month 1 to EoT
Moreover, the course over time for the absolute values and for changes from baseline for 
BCVA variable will be presented graphically for both treatment arms, showing the mean and 
SD of the mean per visit. 
Individual BCVA level profiles will be listed.
Handling of missing values/censoring/discontinuations
For the FAS, the analysis will follow a LOCF approach with the specification that monotone 
missing values will be replaced by the last post-baseline observation prior to the missing 
timepoint. Intermittent missing values will be replaced by the mean of the closest non-missing 
adjacent values.
Supportive analyses
For supportive and sensitivity analyses of the primary analysis where p-values are presented, 
the one-sided non-inferiority p-value for the shifted hypothesis (μDI - μPRN ≤ - Δ) will also be 
provided in addition to the p-value for the (unshifted) null hypothesis.
The primary analysis will be repeated for the PPS (LOCF) using the same methodology as 
outlined in Section 2.6.2. Since this is a non-inferiority trial, the corresponding results 
obtained for the PPS are regarded as of almost equal importance for the interpretation. Any 
major discrepancies in the results across analyses will be investigated as necessary.
The same model as the one used for the primary analysis will be repeated for the FAS on 
observed data (as observed) as well as PPS (as observed). The primary efficacy variable D0 
will be calculated as follows:
D0 = [(sum of non-missing BCVA1, BCVA2, … BCVA12 values) /k] – BCVA0
where k (k = 1, …,12) is the number of non-missing BCVA values between month 1 and 
month 12, inclusively, and BCVA0, BCVA1, … BCVA12 are as defined in Section 2.6.1.
Furthermore, the mean visit-averaged change from baseline in BCVA from month 1 to EoT, 
will be compared between the two treatments based on the assumption of a “Missing at 
Random (MAR)” process, i.e. assuming that the statistical behavior of a patient who drops out 
post-withdrawal is the same as that for a patient remaining in the study and sharing the same 
covariates and the same measurement history. This analysis will be based on a mixed model 
repeated measurement (MMRM). The MMRM model will be fit to all the BCVA data 
collected from month 1 to month 12 inclusive. The MMRM analysis will include subject as a 
random effect, and the following as effects:
Categorical variables

treatment 

center


Novartis
For business use only
Page 29
SAP Addendum
CRFB002DDE26

visit
Continuous variables

baseline BCVA
Interactions

treatment by visit interaction

visit by baseline BCVA interaction
A term for visit will be included in the repeated statement and an unstructured correlation 
matrix will be used thus allowing adjustment for correlations between time points within 
patients. A Kenward-Roger approximation will be used for the denominator degrees of 
freedom.
If the model with the unstructured correlation matrix fails to converge then the following 
correlation structures should be fitted; variance components, compound symmetry, first order 
autoregressive and Toeplitz. The value of the Akaike Information Criteria (AIC) should be 
considered to choose the most appropriate model. Note that, other things being equal, the 
model with the smallest AIC is preferred. In case of inadequate results, further modification of 
the model may be required.
Additional sensitivity analyses of the primary analysis (using the same methodology as 
outlined in Section 2.6) for FAS (LOCF) will be performed:

using all data from baseline to EoS (visit-averaged change from baseline in BCVA 
from month 1 to EoS).
This analysis is meant to additionally include the data collected between EoT and EoS 
for those patients who prematurely discontinue from treatment but stay in the study.

excluding patients who discontinue treatment early but stay in the study

using all data for patients who reach month 12 (i.e. completers, patients who do not 
prematurely discontinue treatment or the study early)
The LS (“adjusted”) means for each treatment arm and estimates of the difference (DI - PRN) 
will be given along with the respective two-sided, 95% CI. P-values will be presented for the 
treatment difference.
The difference in treatment effects will be illustrated graphically using a forest plot for each 
analyzed population for the primary analysis and each sensitivity and supportive analysis: the 
estimates of differences in visit-averaged change from baseline in BCVA from month 1 to the 
timepoint of interest, between the two treatment arms will be presented along with respective 
two-sided 95% CIs.
Furthermore, a frequency table presenting the number and percentage of patients based on 
FAS (LOCF) with a change of 5, 10, or 15 letters in BCVA from baseline at Month 12 will be 
provided. 
KM curves and descriptive statistics will be provided for time to:

first gain in BCVA from baseline of >=10 letters

first gain BCVA from baseline of >=15 letters


Novartis
For business use only
Page 30
SAP Addendum
CRFB002DDE26
for the FAS. The main focus of this study is to understand the effect of the two treatments of 
interest. Therefore, time to first gain >= x letters (where x=10 or 15 letters) will be derived for:
1. up to EoT 
This means: 

if a patient prematurely discontinues treatment (EoT) but stays in the study longer 
(EoS > EoT), then only data up to EoT will be used for calculation and censoring

if a patient prematurely discontinues treatment and the study at the same time, then 
data up to EoS will be used for calculation and censoring

if a patient does not discontinue treatment early, then data up to EoS will be used 
for calculation and censoring
2. up to EoS
In case of no gain of post-baseline BCVA >= x letters (where x=10 or 15 letters), the 
duration will be censored at EoS.
The number and percentage of FAS patients with the aforementioned gain categorizations 
after their first three ranibizumab injections (i.e. change of 5, 10, or 15 letters in BCVA from 
after their first three ranibizumab injections at Month 12) will also be presented.
Descriptive statistics will be produced for the baseline values, absolute values, and the change 
from baseline values to month 12 by overall stability compliance assessment (refer to Section 
2.1.1 for definition). In addition, descriptive statistics will be provided for the visit-averaged 
change from baseline in BCVA from month 1 to EoT (primary outcome) by overall stability 
compliance assessment for the total (not by treatment arm).
Additionally, gender subgroup analysis will be done for the primary analysis (based on FAS 
[LOCF]). Descriptive statistics will be provided for the visit-averaged change from baseline in 
BCVA from month 1 to EoT (primary outcome) for patients with the following characteristics
(see Section 2.1.1 for definitions of these characteristics):

 

the need of additional PRP treatment

experiencing an incident leading to vitrectomy
Analysis of the key secondary objective
There are no key secondary objectives in this study. 
Analysis of secondary efficacy objectives
The analysis of the secondary efficacy objectives will focus on the study eye only and it will
be based on the FAS (LOCF), unless otherwise specified. Only data from baseline to EoT will 
be used for secondary objective analyses, unless specified otherwise. This means: 

if a patient prematurely discontinues treatment (EoT) but stays in the study longer 
(EoS is after EoT), then only data up to EoT will be used

if a patient prematurely discontinues treatment and the study at the same time, then 
data up to EoS will be used

if a patient does not discontinue treatment early, then data up to EoS will be used.


Novartis
For business use only
Page 31
SAP Addendum
CRFB002DDE26
Secondary endpoints
The following secondary efficacy endpoints will be evaluated:

Change of BCVA in ETDRS letters from baseline to month 12

Number of visits, injections and TFIs

Change of CSRT (µm) from baseline to month 12

Change in FCP thickness (µm) from baseline to month 12

Change in 0, 1, 2 or more steps in DRS from baseline to month 12

ANCOVA analysis of primary outcome with the additional covariates: relevant 
changes of HbA1c, blood pressure (systolic, diastolic), and lipid levels (cholesterol, 
HDL-cholesterol, LDL-cholesterol, triglycerides)
Changes in CSRT and FCP thickness will be evaluated by the CRC assessing OCT images. 
Changes in DRS will be evaluated by the CRC scoring CF Photography and FA images and 
will be defined in 5 severity levels:
1. Mild non-proliferative retinopathy (NPDR)
2. Moderate NPDR
3. Severe NPDR
4. Proliferative DR
5. Status post panretinal laser coagulation - not gradable
Statistical hypothesis, model, and method of analysis
Similar to the primary analysis, the secondary analysis will be interpreted in a purely 
descriptive manner due to the reduced sample size although hypothesis testing will still be 
performed for the specific secondary objectives.
For the continuous secondary endpoints BCVA change from baseline, CSRT change from 
baseline, and FCP thickness change from baseline, summary statistics will be produced for the 
baseline values, absolute values and the change from baseline values to month 12. The 
summary statistics for the baseline values, absolute values and the change from baseline 
values to month 12 will also be produced using the unadjusted CSRT and FCP thickness 
values. The course over time for the absolute values and for changes from baseline will be 
presented graphically for the treatment arms for CSRT and FCP thickness variables, showing 
the mean and SD per visit.
Tests comparing the changes in BCVA, CSRT and FCP thickness will be based on ANCOVA 
models, containing the baseline values of the dependent variables as continuous covariates, 
and center and treatment as categorical covariates. The LS (“adjusted”) means for each 
treatment arm and estimates of the difference (DI - PRN) will be given along with the 
respective two-sided, 95% CI. Two-sided p-values will be presented for the treatment 
difference. 
Additional sensitivity analyses of changes in BCVA and CSRT will be performed using all 
data from baseline to EoS. These sensitivity analyses will include descriptive analyses and a 
repeat of the ANCOVA outlined in the previous paragraph.


Novartis
For business use only
Page 32
SAP Addendum
CRFB002DDE26
The total number of injections will be summarized as described in Section 2.5.1.1.
Additionally, the total number of visits and total number of TFIs (see Section 2.1.1 for 
definition of TFI) to month 12 will be summarized for the two treatment arms descriptively. 
Note: All data up to EoS will be used for FAS.
Change in DRS from baseline to month 12 (improvement of 0, 1, 2, and > 2, steps, or loss of 1, 
2, > 2 steps) will be summarized by presenting the number and percentage of patients in each 
treatment arm achieving the endpoint for FAS (LOCF). This improvement/ loss will only be 
derived for those patients with a DRS score of 1, 2, 3, or 4 at baseline and at month 12. In 
addition, a shift table will be produced to summarize the shift from baseline to month 12 in 
DRS score for FAS (LOCF).
Additional ANCOVA models for the primary outcome (visit-averaged change from baseline 
in BCVA from month 1 to EoT) will be performed with the following extra binary covariates
(Yes, No): 

relevant changes of HbA1c (defined as any change of HbA1c (%) from baseline of >
1%)

relevant changes of systolic blood pressure (defined as any change of systolic blood 
pressure (mmHg) from baseline > 30)

relevant changes of diastolic blood pressure (defined as any change of diastolic blood 
pressure (mmHg) from baseline > 20)

relevant changes of cholesterol (defined as any change in cholesterol from baseline of 
(1) for female: <= 2.38 mmol/l; 92 mg/dl or >= 6.06 mmol/l; 234 mg/dl, (2) for male: 
<=2.12 mmol/l; 82 mg/dl or >= 4.97 mmol/l; 192 mg/dl)

relevant changes of HDL-cholesterol (defined as any change in HDL-cholesterol from 
baseline of <= 1.04 mmol/l; 40 mg/dl)

relevant changes of LDL-cholesterol (defined as any change in LDL-cholesterol from 
baseline of >= 3.38 mmol/l; 130 mg/dl)

relevant changes of triglycerides (defined as any change in triglycerides from baseline 
of >= 1.71 mmol/l; 150 mg/dl)
For each ANCOVA model, the LS (“adjusted”) means for each treatment arm and estimates 
of the difference (DI - PRN) will be given along with the respective two-sided, 95% CI
together with two-sided p-values. In order to derive the final ANCOVA model, the following 
steps will be used: 
1. The importance of the individual dependent variables on the primary outcome 
response variable will be testing using the primary ANCOVA model (see Section 2.6.2
for details) for FAS (LOCF). Inclusion in the primary ANCOVA model when p < 0.2. 
2. The backward stepwise regression procedure will be used to choose the optimal set of 
dependent variables from the set of statistically significant dependent variables tested 
in step 1. The significance level to stay in the ANCOVA model is p < 0.05. 
Note: In case of inadequate results, further modification of the model may be required.


Novartis
For business use only
Page 33
SAP Addendum
CRFB002DDE26
Handling of missing values/censoring/discontinuations
For certain secondary endpoints where specified, the analysis will follow a LOCF approach 
(see Section 2.6.3 for details). 
Otherwise the analysis will follow FAS as observed approach. Thus no imputation for missing 
values will be performed.
Safety analyses
Safety parameters will include AEs, intraocular pressure (IOP), vital signs, and laboratory 
results. All safety analyses will be performed using the Safety Set. Patients will be analyzed 
according to treatment received. No missing data will be imputed for safety analyses.
Adverse events
AEs will be deemed treatment emergent if the onset date is on or after the date of first 
treatment with investigational drug. Any AEs recorded prior to the start of investigational 
drug will be listed together with all other AEs. Only TEAEs will be summarized. If any event 
has an incomplete onset date, this will be handled as described in the Appendix 5.1.1.
The period for observing TEAEs for the study eye begins at the first administration of study 
treatment. This safety observation period (days) for the study is defined as: (date of last 
administration of investigational study treatment - date of first administration of study drug) + 
31 (i.e. 30 days after last administration of investigational study treatment).
TEAEs will be presented for both eyes in addition to the study eye and fellow (untreated) eye
separately. AEs will be summarized by presenting for each treatment arm and total the 
number and percentage of patients having any AE (patient counts). Note: The overall TEAE 
summary table will in addition include the number of AEs within each category (event counts). 
AEs will be analyzed separately for ocular and non-ocular AEs (according to the 


Novartis
For business use only
Page 34
SAP Addendum
CRFB002DDE26
investigator’s response to site on the AE eCRF form). Patients who experienced multiple AEs 
for a PT will be counted once, similarly for patients with multiple AEs per SOC. The SOCs 
will be presented in alphabetical order. PTs will be ordered within each SOC for both 
treatment arms and total by decreasing incidence in the total group.
Ocular AEs will be presented separately for the study eye, fellow eye and both eyes. Ocular 
AEs that were recorded in both eyes will be reported for both eyes and additionally separately
for each eye.
AEs that were suspected to be related to study drug or procedures based on the investigator’s 
decision will be summarized. The maximum severity of all TEAEs during the study (safety 
observation period) will be summarized. Summary tables will also be presented for the subset 
of AEs suspected to be treatment related.
Deaths, serious adverse events (SAEs), and AEs leading to discontinuation of investigational 
study treatment will be listed separately and, if appropriate, summarized by primary SOC and 
PT. To summarize, the following AE summaries will be presented for non-ocular, study eye, 
and fellow eye AEs (if applicable) for the TEAE safety observation period:

all AEs

AEs by maximum severity

SAEs

AEs leading to investigational study treatment discontinuation

AEs suspected to be related to investigational study treatment

AEs suspected to be related to ocular injection

AEs suspected to be related to investigational study treatment and/ or ocular injection.
All information pertaining to AEs noted during the study (including AEs during the screening 
period, TEAEs and AEs during the post-treatment period) will be listed by patient, detailing 
AE (e.g., verbatim given by the investigator as well as the SOC and PT according to 
MedDRA), date of starting and ending, severity, suspected relationship (by the investigator) 
to the study drug/ ocular injection, 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.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs 
which are not serious adverse events with an incidence greater than 5% and on treatment 
emergent SAEs and SAEs suspected to be related to study treatment will be provided by SOC 
and PT on the Safety Set.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is <= 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/ SAE suspected to be related to study 
treatment/ non SAE has to be checked in a block e.g., among AE's in a <= 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.


Novartis
For business use only
Page 35
SAP Addendum
CRFB002DDE26
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
The following AE by-patient listings will also be provided:

deaths

SAEs

AEs leading to investigational study treatment discontinuation

AEs related to ocular/ systemic risks

Ocular/ systemic risks will be defined based on important identified and potential 
risks as outlined in the most recent version of the Risk Management Plan (RMP)

all AEs

AEs suspected to be related to investigational study treatment and/ or ocular injection.
Intraocular pressure
IOP absolute values and changes (pre-injection) from baseline by visit and changes from 
pre-dose to post-dose assessments within a visit will be descriptively summarized. 
Additionally, the number and percentage of patients with baseline IOP >= 25 mmHg will be 
presented by visit (pre-injection, post-injection assessment [if applicable]). Summaries will be 
presented separately for the study eye from baseline to EoT period.
All IOP data will be listed for all patients and baseline IOP values >= 25 mmHg will be 
flagged.
Vital signs
Vital signs (sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse, 
weight) will be summarized by descriptive statistics, by visit, presenting absolute and change 
from baseline values. Analysis will be based on the patients in the Safety Set for the baseline 
to EoT period. Using the critical values outlined in Table 2-4, a shift table will be produced to 
summarize the shift from baseline to any vital signs values that are abnormally low or high. 
All data, including data from unscheduled visits, will be considered when identifying 
abnormal values.
By-patient listings will be provided for all vital signs data and values outside the clinical 
normal ranges (see Table 2-4) will be flagged.
Table 2-4
Vital signs critical values
Variable
Type of 
abnormality
Criterion
Systolic blood 
pressure (mmHg)
High
Either ≥180 absolute with an increase from baseline ≥20 
absolute
Low
Either ≤90 absolute with an decrease from baseline ≥20 
absolute
Diastolic blood 
pressure (mmHg)
High
Either ≥105 absolute with an increase from baseline ≥15 
absolute


Novartis
For business use only
Page 36
SAP Addendum
CRFB002DDE26
Variable
Type of 
abnormality
Criterion
Low
Either ≤50 absolute with an decrease from baseline ≥15 
absolute
Pulse rate (bpm)
High
Either ≥120 absolute with an increase from baseline ≥15 
absolute
Low
Either ≤50 absolute with an decrease from baseline ≥15  
absolute
Laboratory evaluation
HbA1c and lipid levels will be presented using standard international (SI) units. Laboratory 
data - observed values or changes from baseline values at each visit - will be summarized 
using descriptive statistics. Analysis will be based on the patients in the Safety Set for the 
baseline to EoT period.
Two sets of shift tables will be provided. First, using the laboratory defined normal ranges
from the raw data, a shift table will be produced to summarize the shift from baseline to any
laboratory values that are abnormally low or high. All data, including data from unscheduled
visits, will be considered when identifying abnormal values.
Second, clinical critical values are defined in Table 2-5. Baseline critical values are defined by 
the absolute values only. Using these critical values, a shift table will be produced to
summarize the shift from baseline to any laboratory values that are abnormally low or high.
All data, including data from unscheduled visits, will be considered when identifying
abnormal values.
By-patient listings will be provided for all laboratory data. Values outside the clinical normal 
ranges will be flagged.
Table 2-5
Critical values for laboratory values
Variable
Type of abnormality
Critical values
Cholesterol
Out of normal range (low): 
female
2.38 mmol/l; 92 mg/dl
Out of normal range (low): male
2.12 mmol/l; 82 mg/dl
Out of normal range (high): 
female
6.06 mmol/l; 234 mg/dl
Out of normal range (high): 
male
4.97 mmol/l; 192 mg/dl
Pathologic value: female and 
male
6.22 mmol/l; 240 mg/dl
Extremely pathologic value: 
female and male
9.07 mmol/l; 350 mg/dl
HDL-Cholesterol
Out of normal range (low)
1.04 mmol/l; 40 mg/dl
Pathologic value (low)
0.91 mmol/l; 35 mg/dl
Extremely pathologic value (low)
0.65 mmol/l; 25 mg/dl
LDL-Cholesterol
Out of normal range (high)
3.38 mmol/l;130 mg/dl


Novartis
For business use only
Page 37
SAP Addendum
CRFB002DDE26
Variable
Type of abnormality
Critical values
Pathologic value (high)
4.94 mmol/l; 190 mg/dl
Extremely pathologic value 
(high)
6.50 mmol/l; 250 mg/dl
Triglycerides
Out of normal range (high)
1.71 mmol/l;150 mg/dl
Pathologic value (high)
3.42 mmol/l; 300 mg/dl
Extremely pathologic value 
(high)
5.13 mmol/l; 450 mg/dl
HbA1c
Out of normal range (high)
6.2%
Pathologic value (high)
6.8%
Extremely pathologic value 
(high)
14.6% (deviation alert above 
12.1%)
Pharmacokinetic endpoints
Not applicable.
PD and PK/PD analyses
Not applicable.
Patient-reported outcomes
Not applicable.
Biomarkers
Not applicable.


Novartis
For business use only
Page 38
SAP Addendum
CRFB002DDE26


Novartis
For business use only
Page 39
SAP Addendum
CRFB002DDE26


Novartis
For business use only
Page 40
SAP Addendum
CRFB002DDE26


Novartis
For business use only
Page 41
SAP Addendum
CRFB002DDE26


Novartis
For business use only
Page 42
SAP Addendum
CRFB002DDE26
Interim analysis
No interim analyses will be performed.
Sample size calculation
A sample size of 133 patients per treatment arm will have 90% power to establish 
non-inferiority at a margin of 4 letters for the 0.5 mg ranibizumab “at investigators discretion” 
dosing regimens in comparison to 0.5 mg ranibizumab PRN in the mean average change in 
BCVA based on a one-sided 0.025 significance level, assuming a treatment difference of 0 
letters, a SD of 10 letters and an underlying normal distribution for an unstratified t-Test 
(nQuery Advisor 7.0). 
The Phase III study (RESTORE) results in the FAS suggest a mean average change in BCVA 
of 6 letters with a SD of about 7-8 letters for ranibizumab. To account for some more 
variability related to the re-treatment concepts and subgroup treated with additional PRP laser 
in this study as compared to RESTORE, a SD of 10 letters is assumed. To account for some 
drop outs 150 patients will be randomized per treatment arm. 
As outlined in the study protocol, section “Summary of protocol amendments” (study protocol 
version no.1 including Amendment 1); further recruitment of patients into this study was 
revised and reduced. New and relevant scientific evidence regarding treatment patterns with 
ranibizumab was published which did not justify continuing the trial with newly included 


Novartis
For business use only
Page 43
SAP Addendum
CRFB002DDE26
patients. Therefore recruitment was terminated at the time when 135 patients were enrolled 
into the study, resulting in a reduced sample size present for analysis. 
As a consequence results are to be interpreted in a purely descriptive manner. With an 
estimate of about 120-150 patients to be enrolled by end of recruitment the expected power 
would be about 55-60% and will be evaluated accordingly.
Change to protocol specified analyses
No change from protocol specified analysis was made.
Appendix
Imputation rules
Adverse Events date imputation
5.1.1.1
AE start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.c )
Uncertain
( 4.c )
After Treatment 
Start
YYYY > TRTY
( 3.a )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
Before imputing AE start date, find the AE start reference date.

If the (imputed) AE end date is complete and the (imputed) AE end date < 
investigational study treatment start date then AE start reference date = min(informed 
consent date, earliest visit date).

Else AE start reference date = investigational study treatment start date
Impute AE start date:


Novartis
For business use only
Page 44
SAP Addendum
CRFB002DDE26
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is 
set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore:
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JULYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the investigational study treatment start 
date year value, the AE started after treatment. Therefore:
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JANYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the investigational study treatment start date 
year value:
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the investigational study treatment start month, 
the imputed AE start date is set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the investigational study treatment start date 
month or greater than the treatment start date month, the imputed AE start date is 
set to the later of (month start point (01MONYYYY), AE start reference date + 1 
day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date.
5.1.1.2
AE end date imputation
For the purpose of date imputation the treatment follow up period date is defined as the last 
available visit date, i.e. including unscheduled visits after the end of study visit.
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
4. If the imputed AE end date is less than the existing AE start date then use AE start 
date as AE end date.


Novartis
For business use only
Page 45
SAP Addendum
CRFB002DDE26
Concomitant medication date imputation
5.1.2.1
CM start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.a )
Uncertain
( 4.c )
After Treatment 
Start
YYYY > TRTY
( 3.a )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date.
2. If the CM start date year value is less than the investigational study treatment start date 
year value, the CM started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid –year point 
(01JULYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the investigational study treatment start 
date year value, the CM started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JANYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).
4. If the CM start date year value is equal to the investigational study treatment start date 
year value:
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior to treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).


Novartis
For business use only
Page 46
SAP Addendum
CRFB002DDE26
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date.
5.1.2.2
CM end date imputation
1. If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed 
CM end date is set to NULL.
2. Else, if the CM end date month is missing, the imputed end date should be set to the 
earliest of the (treatment follow up period date, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death).
4. If the imputed CM end date is less than the existing CM start date, use the CM start 
date as the imputed CM end date.
Medical history date of diagnosis imputation
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date.

If year of diagnosis (or DIAG year) < investigational study treatment start date year 

and DIAG month is missing, the imputed DIAG date is set to the mid-year point 
(01JULYYYY)

else if DIAG month is not missing, the imputed DIAG date is set to the mid-month 
point (15MONYYYY)

If DIAG year = investigational study treatment start date year

and (DIAG month is missing OR DIAG month is equal to investigational study 
treatment start month), the imputed DIAG date is set to one day before 
investigational study treatment start date

else if DIAG month < investigational study treatment start month, the imputed 
DIAG date is set to the midmonth point (15MON YYYY)

else if DIAG month > investigational study treatment start month data error

If DIAG year > investigational study treatment start date year data error


Novartis
For business use only
Page 47
SAP Addendum
CRFB002DDE26
Efficacy variables and populations for analysis
Table 5-3 describes and summarizes the efficacy variables of the study eye, and the
populations for the planned analyses.


Novartis
For business use only
Page 48
SAP Addendum
CRFB002DDE26
Table 5-3
Efficacy variables of the study eye
Analysis
Efficacy 
assessment
Variable
Method
Population 
Time 
Period 
Primary efficacy
BCVA
Visit-averaged 
change 
from 
baseline in BCVA 
ANCOVA1
FAS (LOCF)
Baseline –
EoT 
ANCOVA1
PPS (LOCF) 
Baseline –
EoT
ANCOVA1
FAS (as 
observed) 
Baseline –
EoT
ANCOVA1
FAS (LOCF)  
Baseline –
EoS
MMRM1
FAS (LOCF)
Baseline –
EoT
Secondary efficacy
BCVA
BCVA change from baseline to 
month 12
ANCOVA1
FAS (LOCF)
Baseline -
EoT
BCVA change from baseline to 
month 12 
ANCOVA2
FAS (LOCF)
Baseline -
EoT
CSRT
CSRT change from baseline to 
month 12
ANCOVA1
FAS (LOCF)
Baseline -
EoT
FCP
thickness
FCP
thickness 
change 
from 
baseline to month 12
ANCOVA1
FAS (LOCF)
Baseline -
EoT
1 The model includes the respective baseline variable as a linear covariate and the following 
categorical variables: treatment,  center
2 The model includes the respective baseline variable, relevant changes of HbA1c, blood pressure 
(systolic, diastolic), and lipid levels (cholesterol, HDL-cholesterol, LDL-cholesterol,             
triglycerides) as linear covariates and the following categorical variables: treatment, center
SAS code for analysis
=================================
SAS code for ANCOVA analysis
ANCOVA model will contain ‘treatment’ and ‘center’ as categorical variables, and ‘baseline 
BCVA’ as continuous. For secondary analysis additional linear covariates might be included, 
such as ‘HbA1c’, ‘Blood pressure (systolic, diastolic)’, or ‘Lipid levels (cholesterol, HDL-
cholesterol, LDL-cholesterol, triglycerides)’. 
For the appropriate treatment difference, the treatment arms should be sorted or coded 
appropriately before using this model.
The ANCOVA analysis will be performed using SAS procedure PROC MIXED as below. 
Note that for this illustrative example:

the data are stored in the file data_set

treatmentvar = treatment variable


Novartis
For business use only
Page 49
SAP Addendum
CRFB002DDE26

responsevar = dependent variable

stratavar = stratification variable 

bsl = baseline value of the responsevar 

alpha = significance level (i.e. 0.05 produces two-sided 95% CI)

control = control arm (Ranibizumab 0.5 mg in PRN treatment regime)
PROC MIXED DATA = <data_set>;
CLASS <stratavar> <treatmentvar>;
MODEL <responsevar> = <stratavar> <treatmentvar> <bsl>;
LSMEANS <treatmentvar> / PDIFF = all CL alpha = <alpha> OM;
RUN;
To get the one-sided p-value for the non-inferiority test (margin = 4): add -4 letters to control 
group and re-run the above code with alpha=0.025 and PDIFF=controlu('<control> ').
To get the one-sided p-value for the superiority test (if applicable): re-run the above code with 
alpha=0.025 and PDIFF=controlu('<control> ').
=================================
SAS code for MMRM analysis
Since scheduled visit is in the repeated statement it is important to ensure that each patient has, 
at most, one observation per scheduled visit. This should be checked using PROC SORT and 
NODUPKEY.
To avoid potential problems with a bug in SAS reporting an infinite likelihood, the data will 
be sorted by patient and visit before using PROC MIXED.
For the appropriate treatment difference, the treatment arms should be sorted or coded 
appropriately before using this model.
The comparison of interest is found by using the SAS code below. Note that for this 
illustrative example:

the data are stored in the file data_set

treatmentvar = treatment variable

subjvar = patient identifier

responsevar = dependent variable

stratavar = stratification variable 

visitvar = timepoint variable 

bsl = baseline value of the responsevar

cov = covariance structure

alpha = significance level (i.e. 0.05 produces two-sided 95% CI)

control = control arm (<control>)


Novartis
For business use only
Page 50
SAP Addendum
CRFB002DDE26
PROC SORT DATA = data_set OUT = s_data_set nodupkey;
BY patient visit;
RUN;
PROC MIXED DATA = <s_data_set> METHOD=REML;
CLASS <treatmentvar> <visitvar> <subjvar>;
MODEL <responsevar> = <stratavar> <treatmentvar> <visitvar> 
<treatmentvar>*<visitvar> <bsl> <visitvar>*<bsl> / SOLUTION DDFM = KR;
REPEATED <visitvar> / SUBJECT = <subjvar> TYPE = <cov> r rcorr GROUP = 
<treatmentvar>;
ESTIMATE 'Average Treatment Effect'
                   <treatmentvar> -1 1
                   <treatmentvar>*<visitvar> -0.083 -0.083 -0.083 -0.083 -0.083
                                             -0.083 -0.083 -0.083 -0.083 -0.083
                                             -0.083 -0.083
                                0.083 0.083 0.083 0.083 0.083          
0.083 0.083 0.083 0.083 0.083 0.083 0.083 /cl;
RUN;
Using the slice option above means that the difference between treatment arms will be tested 
for each visit.
To get the one-sided p-value for the non-inferiority test (margin = 4): add -4 letters to control 
group and re-run the above code with alpha=0.025 and PDIFF=controlu('<control> ').
To get the one-sided value for the superiority test (if applicable): re-run the above code with 
alpha=0.025 and PDIFF=controlu('<control> ').
If the model with the unstructured correlation matrix fails to converge then modifications 
shall be made in the following order.
1. Re-instate the GROUP = trtc option and replace un by VC
2. Re-instate the GROUP = trtc option and replace un by CS
3. Re-instate the GROUP = trtc option and replace un by AR(1)
4. Re-instate the GROUP = trtc option and replace un by TOEP
5. Remove the GROUP = trtc option and replace un by VC
6. Remove the GROUP = trtc option and replace un by CS
7. Remove the GROUP = trtc option and replace un by AR(1)
8. Remove the GROUP = trtc option and replace un by TOEP
Removing the GROUP = trtc option assumes that the correlation matrix is equal across the 
treatment arms. The other modifications replace the unstructured correlation matrix by those 
with the following assumptions (in the same order) variance components, compound 
symmetry, first order autoregressive and Toeplitz.
=================================
SAS code for backward stepwise regression analysis
For the appropriate treatment difference, the treatment arms should be sorted or coded 
appropriately before using this model.
The analysis will be performed using SAS procedure PROC GLMSELECT as below. Note 
that for this illustrative example:


Novartis
For business use only
Page 51
SAP Addendum
CRFB002DDE26

the data are stored in the file data_set

treatmentvar = treatment variable

responsevar = dependent variable

stratavar = stratification variable 

bsl = baseline value of the responsevar 

alpha = significance level (i.e. 0.05 produces two-sided 95% CI)

n = the first n effects listed in the MODEL statement which are forced to be included 
in all models
PROC GLMSELECT DATA = <data_set>;
CLASS <stratavar> <treatmentvar>;
MODEL <responsevar> = <stratavar> <treatmentvar> <bsl> / DETAILS = all SELECTION = 
backward INCLUDE = <n>;
LSMEANS <treatmentvar> / PDIFF = all CL alpha = <alpha> OM;
RUN;
=================================
SAS code for Wilcoxon rank sum test
Wilcoxon Rank Sum Test will be presented as a nonparametric comparison additionally to the 
primary analyses.
For the appropriate treatment difference, the treatment arms should be sorted or coded 
appropriately before using this model.
Wilcoxon Rank Sum Test will be presented as a non-parametric comparison additionally to 
the primary analyses.

the data are stored in the file data_set

treatmentvar = treatment variable

responsevar = dependent variable

alpha = significance level
PROC NPAR1WAY DATA = <data_set> HL alpha = <alpha>;
CLASS <treatmentvar>;
VAR <responsevar>;
RUN;
=================================
SAS Codes for Kaplan-Meier Plot
The time to event analysis will be performed using the SAS procedure PROC LIFETEST. 
Note that for this illustrative example:

the data are stored in the file data_set

timevar = survival time

censorvar = censoring variable (Note: 1 indicates a censored time)

stratavar = stratification variable 


Novartis
For business use only
Page 52
SAP Addendum
CRFB002DDE26
ODS GRAPHICS ON;
PROC LIFETEST DATA=<data_set> PLOTS=survival (failure test at 
risk(outside(0.15))=0 to 360 by 30);
TIME <timevar> * <censorvar> (1);
STRATA <stratavar>;
RUN;
The option OUTSIDE(0.15) reserves 15% of the vertical graph window for the at-risk table. It 
can be adjusted.
=================================
SAS Codes for Kaplan-Meier Table
The summary statistics for time to event analysis will be performed using SAS procedure 
PROC LIFETEST.
Note that for this illustrative example:

the data are stored in the file data_set

timevar = survival time

censorvar = censoring variable (Note: 1 indicates a censored time)

stratavar = stratification variable 
PROC LIFETEST DATA = <data_set>;
TIME <timevar> * <censorvar> (1);
STRATA <stratavar>;
ODS OUTPUT CensoredSummary=censorsum
            Means=mean
            Quartiles=quartiles;
RUN;
=================================
SAS Codes for Pearson’s and Spearman’s correlation coefficient
Pearson’s and Spearman’s correlation coefficient will be obtained using SAS procedure 
PROC CORR.
Note that for this illustrative example:

the data are stored in the file data_set

var1 = variable 1 to obtain the correlation of variable 1 and variable 2

var2 = variable 2 to obtain the correlation of variable 1 and variable 2
PROC CORR DATA = <data_set> PEARSON SPEARMAN;
VAR <var1> <var2>;
RUN;


Novartis
For business use only
Page 53
SAP Addendum
CRFB002DDE26
Rule of exclusion criteria of analysis sets 
Table 5-4
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion
from Analyses
I00
Not signed Informed Consent
Excluded from 
all analysis
I01
Subject is less than 18 years of age or age missing.
Not reportable
I02aa
Patients with diabetes but type of diabetes is not known.
Not reportable
I02ab
Patient with no History of diabetes.
Excluded from 
PP analysis
I02b
Glycosylated hemoglobin greater than 12 percent, i.e. 107 mmol per 
mol Hb, at screening Visit 1
Reportable
I03a
Patients without visual impairment due to DME in the study eye
Excluded from 
PP analysis
I03b
Patients without visual impairment due to DME in the fellow eye
Not reportable 
I04a
BCVA less than 24 in the study eye, using ETDRS-like visual acuity 
testing charts at a testing distance of 4 resp. 1 meters (approximate 
Snellen equivalent of 20/32 to 20/320) at screening or baseline
Not reportable 
I04b
BCVA greater than 78 in the study eye, using ETDRS-like visual 
acuity testing charts at a testing distance of 4 resp. 1 meters 
(approximate Snellen equivalent of 20/32 to 20/320) at screening or 
baseline
Excluded from 
PP analysis
I05
Concomitant conditions in the study eye, which prevent improvement 
of visual acuity on study treatment
Excluded from 
PP analysis 
(medical review)
E01aa
Active intraocular inflammation grade trace or above in the study eye
at enrollment.
Excluded from
PP analysis
(medical review) 
E01ab
Active intraocular inflammation grade trace or above in the fellow eye 
at enrollment.
Not reportable
E01a
Women who are pregnant or breast feeding. 
Not reportable
E02
Any active infection in either eye at the time of enrollment e.g. 
conjunctivitis, keratitis, scleritis, endophthalmitis.
Reportable
(medical review)
E03
History of uveitis in either eye at any time.
Not reportable
E04
Structural damage within 0.5 disc diameter of the center of the 
macula in the study eye likely to preclude improvement in VA, incl. 
atrophy of RPE, subretinal fibrosis, laser scar(s).
Excluded from
PP analysis 
(medical review)
E05
Patients with both, a BCVA score of greater than 73 letters and a 
central subfield thickness of less than 300 micro meter in the study 
eye.
Excluded from 
PP analysis 
(medical review)
E06
Uncontrolled glaucoma in either eye at screening. IOP greater than 
24 mmHg on medication or according to investigator judgment.
Excluded from 
PP analysis 
(medical review)
E07
Neovascularization of the iris in either eye.
Not reportable
E08
Vitreous hemorrhage impairing the adequate diagnosis of DME in the 
Excluded from 


Novartis
For business use only
Page 54
SAP Addendum
CRFB002DDE26
Deviation 
ID
Description of Deviation
Exclusion
from Analyses
study eye.
PP analysis
E09
Clinically relevant vitreofoveal adhesion, vitreofoveal traction or 
epiretinal membrane with foveal involvement likely to prevent 
improvement of BCVA, according to investigator opinion.
Not reportable
E10
Proliferative vitreoretinopathy in study eye.
Not reportable
E11
History of retinal detachment, retinal tear or macular hole in the study 
eye.
Not reportable
E12
Neovascularization covering an area greater than or equal to 2 disc 
areas within the macula defined as area with 6mm diameter centered 
on the fovea for study eye.
Not reportable
E13
Patients who are monocular or have a BCVA score in the non-study 
eye less than 24 letters approximate Snellen equivalent of 20 per 320 
at Visit 1.
Not reportable
E14
Any intraocular surgery in the study eye within 4 months prior to 
randomization.
Reportable 
(medical review) 
E15a
Vitrectomy/vitreoretinal surgery - In the medical history or planned for 
study eye.
Reportable 
(medical review)
E15b
Planned vitrectomy or vitrectomy in last 3 months in fellow eye.
Not reportable
E16
Planned medical or surgical intervention during the 12 months study 
period likely to interfere with study schedule or outcomes.
Reportable 
(medical review)
E17
Panretinal or focal or grid laser photocoagulation in study eye within 3 
months prior to randomization unless sufficient documentation of 
laser photocoagulation in that period of time is available.
Reportable 
(medical review)
E18a
Treatment with anti-angiogenic drugs within 1 month for fellow eye 
prior randomization.
Not reportable
E18b*
Treatment with anti-angiogenic drugs within 3 months (84 days) for 
study eye prior randomization.
Excluded from
PP analysis
E19
Use of other investigational drugs at the time of enrollment, or within 
3 months or 5 half-lives from enrollment, whichever is longer.
Reportable 
(medical review)
E20
History of intravitreal corticosteroid treatment in phakic study eye.
Reportable 
(medical review)
E21
Intravitreal corticosteroids in post-cataract surgery study eye (aphakic
or pseudophakic, without damaged posterior capsule) within 3 
months or 6 months for dexamethasone implant (Ozurdex®) or 3 
years for fluocinolone implant (Iluvien®) prior to randomization.
Excluded from
PP analysis
E22
Ocular conditions in the study eye that require chronic concomitant 
therapy with topical ocular corticosteroids.
Reportable 
(medical review)
E23
Stroke less than 4 months prior to screening.
Not reportable
E24
Renal failure requiring dialysis or renal transplant.
Not reportable
E25
Untreated diabetes mellitus.
Not reportable
E26
BP defined as systolic value of greater than 160 mm Hg or diastolic 
value greater than 100 mm Hg at screening or randomization.
Not reportable
E27
Conditions that require chronic concomitant therapy with systemically 
administered corticosteroids.
Reportable 
(medical review)
E28
Current use of Medications known to be toxic to the lens, retina or 
Reportable 


Novartis
For business use only
Page 55
SAP Addendum
CRFB002DDE26
Deviation 
ID
Description of Deviation
Exclusion
from Analyses
optic nerve, including Deferoxamine, Chloroquine or 
hydroxychloroquine, Plaquenil, Tamoxifen, Phenothiazines and 
Ethambutol.
(medical review)
E29
Use of any systemic anti VEGF drugs within 3 months prior to 
Screening.e.g. bevacizumab, ziv aflibercept.
Excluded from 
PP analysis
E30
Known hypersensitivity to fluorescein or ranibizumab or any 
component thereof or drugs of similar chemical classes.
Not reportable
E31
Disease severity/medical condition/ treatment expected to progress,
recur, or change to an extent may bias the assessment of clinical 
status of patient or special risk to a significant degree.
Reportable
(medical review)
D01
MH or AE - Rhegmatogenous retinal detachment or Stage 3 or 4 
macular hole in the study eye and no treatment discontinuation.
Excluded from 
PP analysis 
(medical review)
D02
MH or AE -  Transient ischemic attack or a stroke during the study 
and no treatment discontinuation
Not reportable
D03
Pregnancy but patient not discontinued from trial.
Excluded from 
PP analysis
D04
Vitrectomy that did not lead to discontinuation of study treatment.
Excluded from
PP analysis
S01
Patient received Ranibizumab from another study or as commercially 
available Lucentis
Not reportable
S02
Study task injection of ranibizumab was performed by untrained site 
personnel.
Not reportable
S03
Patient received study medication which was outside the allowed 
temperature range and should have not been used any more 
according to guidelines or QP decision.
Reportable 
(medical review)
M01
Concurrent use of any anti-VEGF agents either systemic or in the 
study eye (only permitted in the fellow eye).
Excluded from 
PP analysis
M02
Concurrent use of peribulbar or intraocular corticosteroids in study 
eye.
Excluded from
PP analysis
M03
Concurrent use of intraocular corticosteroids inserts in study eye.
Excluded from
PP analysis
M04
Systemic medications known to be toxic to the lens, retina or optic 
nerve, including Deferoxamine, Chloroquine or hydroxychloroquine,
Tamoxifen, Phenothiazines and Ethambutol.
Reportable 
(medical review)
M05
Treatment with glitazones or fingolimod when newly started during 
the study.
Reportable 
(medical review)
M06
Other investigational drugs and interventions of any type.
Excluded from
PP analysis
 
O02
Missing FLA assessment at visit 1 for both eyes.
Not reportable
O03
Missing FLA assessment at visit 14 for both eyes.
Not reportable
O04a
Missing FP assessment at visit 1 for both eyes.
Not reportable
O04b
Missing FP assessment at EOS visit for both eyes.
Not reportable


Novartis
For business use only
Page 56
SAP Addendum
CRFB002DDE26
Deviation 
ID
Description of Deviation
Exclusion
from Analyses
O05
Missing BCVA in study eye at any visit.
Not reportable
O06
Missing BCVA in fellow eye at any Screening, EOS and EOT visits.
Not reportable
O07
Missing OCT assessment in study eye at any visit.
Not reportable
O08
Missing OCT assessment in fellow eye at Screening, EOS and EOT 
visits.
Not reportable
O09a
Intraocular Pressure was not measured prior treatment for study eye.
Not reportable
O09b
Intraocular Pressure was not measured after treatment for study eye.
Not reportable
O10
Inadequate training of Investigators during study conduct.
Not reportable
O12
Screening not 28 to 3 days before Baseline.
Not reportable
O14
End of Study Visit not after last treatment of study medication.
Not reportable
O15
Focal or grid laser photocoagulation done prior 3 months after 
baseline.
Reportable 
(medical review)
O16
Any Treatment cycle (PRP) was not completed within 6 weeks
Reportable
(medical review)
O17
Panretinal Photocoagulation at baseline or at least within 3 months 
after randomization in both arms for study eye for respective patients
Reportable 
(medical review)
O19
PDR laser spots smaller than 500 micro meter for respective patients
Not reportable
O20
Less than 12 weeks between PRP-treatments for respective patients
Not reportable
O21
VA examination done by non-certified personnel for both eyes or 
study eye only.
Not reportable
O22
OCT examination done by personnel not certified for study.
Not reportable
O23
OCT examination done with a device not registered for study.
Not reportable
O25
FP examination done with a device not registered for study.
Not reportable
 
 
O28
BCVA examination done in a non-certified room.
Not reportable
 
O31
General GCP or CSP compliance issue.
Not reportable
O32
VA assessor did not change from Visit 1 to Visit 4 (same at any 2 
consecutive visits up to V4).
Not reportable
O33
VA assessor did not change from Visit 5 onwards (same at any 2 
consecutive visits from V5 onwards).
Reportable
O35**
BCVA measurement was performed 2 days later then visit 1. V1 was 
split in 2 days.
Not reportable
O37
Same BCVA-Assessor at consecutive months visit 5 onwards.
Reportable
O39
BCVA assessor, who performed other study tasks and was 
subsequently unmasked to treatment arm, was still active as BCVA 
assessor.
Reportable


Novartis
For business use only
Page 57
SAP Addendum
CRFB002DDE26
Deviation 
ID
Description of Deviation
Exclusion
from Analyses
O40
Minimum PRP treatment of 1200 burns for study eye was not given 
for respective patients.
Reportable 
(medical review)
O41
Subjects who had completed trial and have number of days 
difference between V2 to V14 (EOS) is above 393 days. 
Excluded from 
PP analysis
O42
Minimal Injection window period must be 28 days.
Not reportable
* In PD E18b the 3 months criterion was clarified to be 84 days (which is based on 7 days by 4 weeks 
by 3 months)
** PD O34 was retired as a PD and will only be handled as an edit check by data management in the 
database
Reference
(1) CRFB002DDE26 Protocol 

CREDI 
Projects/R/RFB002D/CREDI 
Studies/RFB002DDE26/CSP 
(Clinical 
Study Protocol) – CRFB002DDE26_CSP_V01
(2) CRFB002 Project Master Analysis Plan (MAP) Version 2.0

CREDI Projects/R/RFB002A/Administrative files/CIS (Clinical Information 
Sciences)/Biostatistics 
–
CRF002 
MAP 
Module 
3 
Detailed 
statistical 
methodology_v2
(3) Han IC, Jaffe GJ (2009) Comparison of Spectral- and Time-Domain Optical Coherence 
Tomography for Retinal Thickness Measurements in Healthy and Diseased Eyes. 
American Journal of Ophthalmology 147:847-858.(4) Lang, GE et al. (2013) Two-Year 
Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema: Interim Analysis 
of the RESTORE Extension Study. Ophthalmology 120(10): 2004-12
(5) Mitchell P et al. (2011) The RESTORE study: ranibizumab monotherapy or combined 
with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 118.4: 
615-25
(6) Mylonas et al. (2009) Comparison of retinal thickness measurements and segmentation 
performance of four different spectral and time domain OCT devices in neovascular 
agerelated macular degeneration. British Journal of Ophthalmology 93:1453–1460.
(7) Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner 
O, Bouazza AS, Shen H, Osborne A, Mitchell P: Three-Year Outcomes of Individualized 
Ranibizumab Treatment in Patients with Diabetic Macular Edema: The RESTORE 
Extension Study. Ophthalmology 2014.