Conditions: Diabetic Macular Edema
Keywords: Diabetic macular edema, DME, ranibizumab, wait and extend
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
To explore a more clinical feasible treatment regime with ranibizumab for DME to provide satisfactory treatment effect with a lower number of visits and injections.

Detailed description:
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with prevalence estimates ranging between 2 to 5% of the world's population. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular complications in patients with diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually leading to blindness. DME is a frequent manifestation of DR and is the major cause of visual loss in patients with DR. If left untreated, \>50% of patients lose \>2 lines of visual acuity (VA) within 2 years. DME mostly affects the working-age population, imposing a significant burden both on society and on individual patients - a burden that is expected to increase with the rising prevalence of diabetes.

Arms:
arm 1: Ranibizumab (Anti VEGF) 0.5mg treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month arm 2: Ranibizumab (Anti VEGF) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.

Interventions: intervention 1: Labeled regime arm intervention 2: Wait and Extend regime arm
Intervention descriptions: intervention 1: Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month. intervention 2: Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.

Protocol document:
Prot_001.pdf: 
Clinical Development 
[RFB002/Ranibizumab] 
Clinical Trial Protocol [CRFB002DTR01] / NCT02262260 
A Randomized, Open-label Non-inferiority Study to 
Compare Safety and Efficacy of Labeled Versus Wait and 
Extend Regimen of Lucentis (ranibizumab) in Turkish 
Patients With Visual Impairment Due to Diabetic Macular 
Edema. 
Authors 
Study coordinator: 
Dr. 
 
Prof.Dr. 
 
Document type: 
Clinical Trial Protocol 
Version number: 
4.0 
Development phase: 
III 
Release date: 
07.Apr.2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 


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Table of contents 
List of figures ....................................................................................................................... 4 
List of abbreviations ............................................................................................................ 5 
Glossary of terms ................................................................................................................. 6 
Protocol synopsis ................................................................................................................. 7 
Exclusion criteria ................................................................................................................. 9 
1 
Introduction ........................................................................................................................ 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose ................................................................................................................... 12 
2 
Study objectives ................................................................................................................. 13 
2.1 
Primary and key secondary objectives ................................................................... 13 
2.2 
Secondary objectives ............................................................................................. 13 
2.3 
Exploratory objectives ........................................................................................... 13 
3 
Investigational plan ............................................................................................................ 13 
3.1 
Study design ........................................................................................................... 13 
3.2 
Rationale of study design ....................................................................................... 15 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ...... 15 
3.4 
Purpose and timing of interim analyses/design adaptations .................................. 15 
3.5 
Risks and benefits .................................................................................................. 16 
4 
Population .......................................................................................................................... 16 
4.1 
Inclusion criteria .................................................................................................... 16 
4.2 
Exclusion criteria ................................................................................................... 17 
5 
Treatment ........................................................................................................................... 17 
5.1 
Protocol requested treatment .................................................................................. 17 
5.1.1 
Investigational treatment ....................................................................... 17 
5.2 
Treatment arms ...................................................................................................... 18 
5.3 
Treatment assignment, randomization ................................................................... 18 
5.4 
Treatment blinding ................................................................................................. 18 
5.5 
Treating the patient ................................................................................................ 19 
5.5.1 
Patient numbering .................................................................................. 19 
5.5.2 
Dispensing the investigational treatment ............................................... 19 
5.5.3 
Handling of study treatment .................................................................. 19 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 20 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ......... 20 
5.5.6 
Rescue medication ................................................................................. 20 
5.5.7 
Concomitant treatment .......................................................................... 21 
5.5.8 
Prohibited Treatment ............................................................................. 21 


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5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 22 
5.5.10 
Study completion and post-study treatment .......................................... 23 
5.5.11 
Early study termination ......................................................................... 23 
6 
Visit schedule and assessments ......................................................................................... 23 
6.1 
Information to be collected on screening failures .................................................. 25 
6.2 
Baseline characteristics .......................................................................................... 25 
6.3 
Treatment exposure and compliance ...................................................................... 25 
6.4 
Efficacy ....................................................................................................................... 25 
Visual Acuity ......................................................................................................... 25 
Color Fundus Photography and Fluorescein Angiography .................................... 25 
Optical Coherence Tomography ............................................................................ 26 
6.4.1 
Appropriateness of efficacy assessments ............................................... 26 
6.5 
Safety ..................................................................................................................... 26 
6.5.1 
Vital signs .............................................................................................. 26 
6.5.2 
Body Mass Index ................................................................................... 26 
6.5.3 
Laboratory evaluations .......................................................................... 26 
6.5.4 
Electrocardiogram (ECG) ...................................................................... 27 
6.5.5 
Pregnancy and assessments of fertility .................................................. 27 
6.5.6 
Appropriateness of safety measurements .............................................. 27 
6.6 
Other assessments .................................................................................................. 27 
Standard Ophthalmological Examination .......................................................................... 27 
Tonometry ......................................................................................................................... 27 
6.6.1 
Resource utilization ............................................................................... 27 
6.6.2 
Health-related Quality of Life .................................................................. 27 
6.6.3 
Pharmacokinetics ................................................................................... 28 
6.6.4 
Pharmacogenetics/pharmacogenomics ....................................................... 28 
6.6.5 
Other biomarkers ................................................................................... 28 
7 
Safety monitoring .............................................................................................................. 28 
7.1 
Adverse events ....................................................................................................... 28 
7.2 
Serious adverse event reporting ............................................................................. 30 
SAE Reporting to Ministry of Health and Ethical Committee .......................................... 31 
7.3 
Pregnancy reporting ............................................................................................... 31 
8 
Data review and database management ............................................................................. 31 
8.1 
Site monitoring ...................................................................................................... 31 
8.2 
Data collection ....................................................................................................... 32 
8.3 
Database management and quality control............................................................. 32 
8.4 
Data Monitoring Committee .................................................................................. 33 


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8.5 
Adjudication Committee ........................................................................................ 33 
9 
Data analysis ...................................................................................................................... 33 
9.1 
Analysis sets .......................................................................................................... 33 
9.2 
Patient demographics and other baseline characteristics........................................ 33 
9.3 
Treatments ............................................................................................................. 33 
9.4 
Analysis of the primary and key secondary variable(s) ......................................... 33 
9.4.1 
Variable(s) ............................................................................................. 33 
9.4.2 
Statistical model, hypothesis, and method of analysis ........................... 33 
9.4.3 
Handling of missing values/censoring/discontinuations ........................ 33 
9.4.4 
Supportive analyses ............................................................................... 34 
9.5 
Analysis of secondary variables ............................................................................. 34 
9.5.1 
Efficacy variables .................................................................................. 34 
9.5.2 
Safety variables ..................................................................................... 34 
9.5.3 
Resource utilization ............................................................................... 34 
9.5.4 
Health-related Quality of Life .................................................................. 34 
9.5.5 
Pharmacokinetics ................................................................................... 34 
9.5.6 
Pharmacogenetics/pharmacogenomics .................................................. 35 
9.5.7 
Biomarkers ............................................................................................ 35 
9.5.8 
PK/PD ................................................................................................... 35 
9.6 
Interim analyses ..................................................................................................... 35 
9.7 
Sample size calculation .......................................................................................... 35 
10 Ethical considerations ........................................................................................................ 35 
10.1 
Regulatory and ethical compliance ........................................................................ 35 
10.2 
Informed consent procedures ................................................................................. 35 
10.3 
Responsibilities of the investigator and HA/IEC ................................................... 36 
10.4 
Publication of study protocol and results ............................................................... 36 
11 Protocol adherence ............................................................................................................. 36 
11.1 
Protocol Amendments ............................................................................................ 37 
12 References.......................................................................................................................... 37 
List of figures 
Figure 3-1 
Study design .......................................................................................... 15 


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List of abbreviations 
ADA 
American Diabetes Association 
 
AE 
Adverse Event 
AMD 
Age related macular degeneration 
BCVA 
Best corrected visual acuity 
CRF 
Case report form 
CRO 
Contract Research Organization 
CRT 
Central retinal thickness 
DBP 
DME 
DR 
Diastolic blood pressure 
Diabetic Macular Edema 
Diabetic Retinopathy 
ECG 
Electrocardiogram 
ETDRS 
The Early Treatment Diabetic Retinopathy Study 
FFA 
Fundus fluorescein angiography 
FSH 
HA 
Follicle-stimulating hormone 
Health Authority 
IEC 
Independent Ethics Committee 
logMAR 
Logarithm of the minimum angle of resolution 
MedDRA 
Medical dictionary for regulatory activities 
OCT 
Ocular coherence tomography 
RPE 
Retinal pigment epithelium 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 
VFQ-25 
Visual Function Questionnaire 
WOCBP 
Women of childbearing potential 


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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 
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Subject Number 
A number assigned to each patient who enrolls into the 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 


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Protocol synopsis 
Protocol number 
CRFB002DTR01 
Title 
A randomized, open-label non-inferiority study to compare safety and 
efficacy of labeled versus wait and extend regimen of Lucentis 
(ranibizumab) in Turkish patients with visual impairment due to diabetic 
macular edema. 
Brief title 
Study of efficacy and safety of Ranibizumab in Turkish patients with visual 
impairment due to diabetic macular edema. 
Sponsor and Clinical 
Phase 
Novartis / Phase III 
Investigation type 
Drug Research 
Study type 
Interventional Study 
Purpose and rationale 
The purpose of this study is to demonstrate the non-inferiority of “wait and 
extend” regimen of ranibizumab to labeled posology in Turkish patients 
with visual impairment due to diabetic macular edema with respect to the 
mean change in BCVA at 12th month from baseline.. 
Data from 
RESOLVE 
and RESTORE trials 
supporting monthly 
assessments and PRN Lucentis injections assumed to be considered as 
“gold standard” for future treatment of patients with visual impairment due 
to diabetes macula edema as it is for wet AMD. However, there is a need 
to explore a more clinical feasible treatment regime to provide satisfactory 
treatment effect with a lower number of visits and injections. A “wait and 
extend” regimen has been demonstrated efficient for treatment of wAMD in 
SALUTE study as mentioned above and found to be safe and tolerable. 
The rationale of this pilot study is to show that similar approach is 
applicable in treatment of DME. 
Primary Objective(s) 
and Key Secondary 
Objective 
The primary objective of this study is to demonstrate the non-inferiority of 
“wait and extend” regimen of ranibizumab to labeled posology in Turkish 
patients  with  visual  impairment  due  to  diabetic  macular  edema  with 
respect to the mean change in BCVA at 12th month from baseline.. 
Secondary Objectives 
• 
to compare mean change in CRT at 12th  month from baseline 
between two groups with OCT 
• 
to  assess  the  number  of  injections  needed  over  a  12-month 
treatment period with a “wait and extend” dosing regimen 
• 
to assess the number of visits needed over a 12-month treatment 
period with a “wait and extend” dosing regimen 
• 
to evaluate the number of patients with improvement in BCVA 
from baseline 
• 
to evaluate the number of patients with improvement of 5 or more 
letters from baseline 


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• 
to evaluate the number of patients with improvement of 10 or more 
letters from baseline 
• 
to evaluate the number of patients with improvement of 15 or more 
letters from baseline 
• 
to  evaluate  the  safety  of  intravitreal  injections  of  Lucentis 
(ranibizumab) in patients with DME 
• 
to describe the change in Patient reported functional ability of 
Lucentis-treated patients. 
Study design 
This is a randomized controlled, multicenter, 12 month study of Lucentis 
(ranibizumab) that the consenting patients will participate in a screening 
period and will be evaluated for their eligibility to enroll the study. After the 
screening period and the eligibility assessment of the patient, only one eye 
will be selected / treated as the study eye. After eligibility confirmation at 
baseline, patients will be randomized into one of the treatment arms as 
below: 
• 
Arm 1 - Labeled regime arm: Treatment will be given monthly and will 
be continued until maximum visual acuity is achieved (the patient’s 
visual acuity is stable for three consecutive monthly assessments 
performed while on ranibizumab treatment). Thereafter patients should 
be monitored monthly for visual acuity. 
Treatment will be resumed when monitoring indicates loss of visual 
acuity due to DME. Monthly injections should then be administered 
until stable visual acuity is reached again for three consecutive 
monthly assessments (implying a minimum of two injections). The 
interval between two doses should not be shorter than 1 month. 
• 
Arm 2 - Wait and Extend regime arm: Lucentis (ranibizumab) 0.5 mg 
will be injected subsequently at baseline, month 1 and 2. After the 
three initial loading doses, patients will be called for the control visits 1 
month later. If the visual acuity has reached a stable level and there is 
no sign of edema on OCT, patients will not receive intravitreal injection 
and will be called to come back 6 weeks later. The interval is increased 
by 2 weeks until a maximum of 8 weeks as long as the patient 
presents as stable regarding visual acuity, central retinal thickness and 
clinical findings. If there is a negative change, the interval is shortened 
back to 4 weeks. 
Population 
The study population will consist of male and female patients (over 18 
years old) admitted to hospital with Type 1 or Type 2 diabetes mellitus 
(according to ADA or WHO guidelines) with HbA1c not more than 12.0% 
at screening (Visit 1). Patients should be on diet, exercise, and/or 
pharmacological treatment for diabetes and should have a visual 
impairment due to focal or diffuse macular edema with center involvement 
in at least  one eye,  as demonstrated with  color fundus photography, 
fluorescein angiography and OCT within 28 days of the baseline 
treatment. It is aimed to randomize a total of 86 patients in approximately 
12 centers in Turkey. Since a 20% screening failure rate is expected, 104 


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patients have to be screened. 
Inclusion criteria 
1. 
Written informed consent must be obtained before any assessment is 
performed. 
2. 
Male or female patients >18 years of age who have signed an 
informed consent 
3. 
Patients with Type 1 or Type 2 diabetes mellitus (according to ADA 
or WHO guidelines) with HbA1c not more than 12.0% at screening 
(Visit 1). Patients should be on diet, exercise, and/or pharmacological 
treatment for diabetes. 
4. 
Patients with visual impairment due to focal or diffuse macular edema 
with center involvement in at least one eye, as demonstrated with 
color fundus photography, fluorescein angiography and OCT within 
28 days of the baseline treatment. If both eyes are eligible, the one 
with the worse visual acuity, as assessed at Visit 1, will be 
selected for study treatment unless, based on medical reasons, the 
investigator deems the other eye the more appropriate candidate for 
study treatment. The study eye must fulfill the following criteria at 
Visit 1: 
• 
BCVA score between 78 and 39 letters, inclusively, using 
ETDRS-like visual acuity testing charts at a testing distance 
of 4  meters (approximate Snellen equivalent of 20/32 to 
20/160) 
• 
Decrease in vision is due to DME and not due to other 
causes, in the opinion of the investigator 
Exclusion criteria 
Exclusion criteria 
1. 
Concomitant conditions in the study eye according to defined criteria 
such as infection, inflammation, uncontrolled glaucoma 
2. 
Active proliferative diabetic retinopathy or evidence of vitreomacular 
traction in the study eye 
3. 
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 
4. 
The history of vitrectomy in the study eye. 
5. 
Concomitant systemic condition according to defined criteria, eg. 
history of stroke, uncontrolled diabetes, renal failure, unsatisfactory 
controlled hypertension 
6. 
Use of other investigational drugs within 5 half-lives of enrollment, or 
within 30 days until the expected PD effect has returned to baseline, 
whichever is longer. 
7. 
History of hypersensitivity to any of the study drugs or to drugs of 
similar chemical classes. 
8. 
History of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin), treated or untreated, within the 
past 5 years, regardless of whether there is evidence of local 
recurrence or metastases. 
9. 
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 laboratory test. 
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. 


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Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks ago. 
In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
Investigational and 
reference therapy 
The investigational drug in this study will be ranibizumab 0.5 mg. No 
additional treatment beyond investigational treatment is requested for this 
trial. 
Efficacy assessments 
• 
Mean change in Best-corrected visual acuity (BCVA) with ETDRS- 
like chart at a starting distance of 4 meters, at 12th month from 
baseline 
• 
Mean change in CRT (µm) by Optical coherence tomography at 
12th month from baseline 
• 
Mean no. of injections over a 12-month treatment period 
• 
Mean no. of visits over a 12-month treatment period 
• 
Proportion of patients who gained ≥0, ≥5, ≥10 and ≥15 letters in 
BCVA at 12th month 
• 
Mean change in VFQ25 scores at 12th month from baseline 
Safety assessments 
• 
Incidence of adverse events (AEs) and serious AEs (SAEs), by 
ophthalmic examinations and IOP measurements, and by changes in 
vital signs and laboratory parameters over the 12-month assessment 
period. 
Other assessments 
There is no other planned analysis to be performed for this study. 
Data analysis 
A sample size of 86 (43 for each treatment arm) can achieve 90% power 
to detect non-inferiority limit of 5 letter between treatment arm when 
significance level of the test is 0.025 and the mean (standard deviation) 
letter change of labeled regime arm will be around 7 (7). To eliminate the 
effects of incomplete data which are expected in 1 year follow-up period, a 
priori 20% of drop-out rate is accepted; therefore at least 104 patients (52 
for each treatment arm) will be included to the study. 
Key words 
Optic Coherence Tomography, Diabetic Macular Edema, Ranibizumab, 
Tolerability, Safety, Wait and Extend 


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1 
Introduction 
1.1 
Background 
 
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with 
prevalence estimates ranging between 2 to 5% of the world’s population. Diabetic retinopathy 
(DR) and diabetic macular edema (DME) are common microvascular complications in patients 
with diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually 
leading to blindness. DME is a frequent manifestation of DR [Riordan-Eva, 2004] and is the 
major cause of visual loss in patients with DR. 
 
If left untreated, >50% of patients lose >2 lines of visual acuity (VA) within 2 years. DME 
mostly affects the working-age population, imposing a significant burden both on society and 
on individual patients - a burden that is expected to increase with the rising prevalence of 
diabetes [Bandello, 2012] 
 
Diabetic macular edema (DME) can occur at any stage of non-proliferative and proliferative 
diabetic retinopathy. It is characterized by a swelling of the macular area that normally 
accounts for high-resolution visual acuity (VA), and DME therefore leads to visual 
deterioration. Clinically significant DME (CSME) is defined as retinal thickening with or 
without hard exudates within one diameter of the macular center and results in visual 
impairment when the foveola is involved. This is referred to as CSME with center 
involvement (CSME-CI) [Lang, 2012]. 
 
 
One important aspect of the pathophysiology of DME is that cytokine signaling and 
expression are deregulated in patients with diabetic retinopathy. The permeability of retinal 
endothelial cells (REC) is controlled by VEGF and regulated by its binding to the VEGF 
receptor 2. DME results from a breakdown of the blood-retinal barrier and leads to retinal 
thickening caused by an accumulation of fluid and molecules in the retina. The leakage can 
arise from microaneurysms or capillaries. The primary endogenous mediator of DME is 
VEGF, a glycoprotein that is secreted by REC, pericytes and pigment epithelial cells. REC 
dysfunction seems to be an important step in the development of DME. Hyperglycemia and 
hypoxia-induced VEGF release are important confounding factors [Lang, 2012]. 
 
 
For the last decades, laser was the gold standard for the treatment of patients with CSME. 
This treatment, however, is destructive and it rather prevents further visual deterioration than 
improves vision. Therefore, new treatment modalities were developed to overcome the unmet 
medical need to restore vision [Lang, 2012]. 
 
 
Ranibizumab (Lucentis) is a recombinant humanized IgG1 κ isotype monoclonal antibody 
fragment (Fab) that selectively binds VEGF. Ranibizumab (intravitreal injections of 0.5 mg) 
is approved for the treatment of neovascular age-related macular degeneration (AMD), the 
treatment of visual impairment due to diabetic macular edema (DME) and the treatment of 


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visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or 
central RVO) in anumber of countries worldwide [Product information]. 
Five trials, ie, two DRCR.net trials, RESTORE, RISE, and RIDE, have provided level I 
evidence supporting use of ranibizumab for the treatment of DME, and two additional trials 
have provided level II evidence. These trials demonstrate that ranibizumab therapy for DME 
is safe and effective for two years [Stewart, 2013] The approval of ranibizumab for patients 
with visual impairment due to DME with center involvement has improved the visual 
prognosis and offers therapy for an up to now unmet medical need [Lang, 2012]. 
The recommended dose for Lucentis is 0.5 mg given monthly as a single intravitreal injection. 
Treatment is continued until maximum visual acuity is achieved i.e the patient’s visual acuity 
is stable for three consecutive monthly assessments performed while on ranibizumab 
treatment. Thereafter patients should be monitored monthly for visual acuity. Treatment is 
resumed when monitoring indicates loss of visual acuity due to DME Monthly injections 
should then be administered until stable visual acuity is reached again for three consecutive 
monthly assessments. The interval between two doses should not be shorter than 1 
month.However, there is a need to explore a more clinical feasible treatment regime to 
provide satisfactory treatment effect with a lower number of visits and injections [Product 
information} 
A “wait and extend” regimen has been demonstrated efficient for treatment of wAMD in 
SALUTE study as mentioned above and found to be safe and tolerable [ASRS 2013]. The 
rationale of this pilot study is to show that similar approach is applicable in treatment of 
DME. 
According to the SALUTE study performed in Turkey with 104 screened patients, 
Ranibizumab usage with Wait & Extend or Treat & Observe approach provided improvements 
in terms of best corrected visual acuity and central retinal thickness. and no significant 
differences between treatment approaches were found. In per protocol population; visit count 
in Wait & Extend group is significantly lower than Treat & Observe group. In conclusion, 
using ranibizumab in patients with choroidal neovascularisation due to AMD with Wait & 
Extend regimen seems to be as efficient, safe and tolerable as Treat & Observe regimen 
with less number of visits [ASRS 2013]. 
The rationale of this pilot study is to show that similar approach is applicable in treatment of 
DME. 
 
1.2 
Purpose 
The purpose of this study is to demonstrate the non-inferiority of “wait and extend” regimen 
of ranibizumab to labeled posology in Turkish patients with visual impairment due to diabetic 
macular edema with respect to the mean change in BCVA at 12th month from baseline.. 


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2 
Study objectives 
2.1 
Primary and key secondary objectives 
The primary objective of this study is to demonstrate the non-inferiority of “wait and extend” 
regimen of ranibizumab to labeled posology in Turkish patients with visual impairment due to 
diabetic macular edema with respect to the mean change in BCVA at 12th month from 
baseline. 
 
2.2 
Secondary objectives 
 
• to compare mean change in CRT at 12th month from baseline between two groups with 
OCT 
• to assess the number of injections needed over a 12-month treatment period with a “wait 
and extend” dosing regimen 
• to assess the number of visits needed over a 12-month treatment period with a “wait and 
extend” dosing regimen 
• to evaluate the number of patients with improvement in BCVA from baseline 
• to evaluate the number of patients with improvement of 5 or more letters from baseline 
• to evaluate the number of patients with improvement of 10 or more letters from baseline 
• to evaluate the number of patients with improvement of 15 or more letters from baseline 
• to evaluate the safety of intravitreal injections of Lucentis (ranibizumab) in patients with 
DME 
• to describe the change in Patient reported functional ability of Lucentis-treated patients. 
 
2.3 
Exploratory objectives 
Not Applicable 
 
3 
Investigational plan 
3.1 
Study design 
This is a randomized controlled, multicenter, 12 month study of Lucentis (ranibizumab) that 
the consenting patients will participate in a screening period and will be evaluated for their 
eligibility to enroll the study. After the screening period and the eligibility assessment of the 
patient, only one eye will be selected / treated as the study eye. After eligibility confirmation 
at baseline, patients will be randomized into one of the treatment arms as below: 


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• Arm 1 - Labeled regime arm: Treatment will be given monthly and will be continued until 
maximum visual acuity is achieved (the patient’s visual acuity is stable for three 
consecutive monthly assessments performed while on ranibizumab treatment). Thereafter 
patients should be monitored monthly for visual acuity. 
 
• Retreatment criteria: 
 
o According to this protocol VA stability means BCVA ≥ 84 letters (approximate 
Snellen equivalent of 20/20) or OCT <300 microns in the last 2 consecutive visits 
or no improvement can be achieved according to the investigators evaluation 
regarding VA and OCT measures in the last 2 visits . Stable patients do not require 
reinjection and should be evaluated in the next visit for reinjection. 
 
o If VA decreases ≥ 5 letters compared to previous visit and OCT is >300 microns, 
patients will be retreated. 
 
o If VA decreases ≥5 letters compared to the previous visit or CRT increases >50 
microns compared to the previous visit, patients will be retreated. 
 
o After 3 monthly injections of the investigational drug laser photocoagulation can 
be administered if VA worsens ≥10 letters and/or CRT increases >100 microns. 
• The interval between two doses should not be shorter than 1 month. 
 
• Arm 2 - Wait and Extend regime arm: Lucentis (ranibizumab) 0.5 mg will be injected 
subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will 
be called for the control visits 1 month later. If the visual acuity has reached a stable level 
and there is no sign of edema on OCT, patients will not receive intravitreal injection and 
will be called to come back 6 weeks later. The interval is increased by 2 weeks until a 
maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, 
central retinal thickness and clinical findings. If there is a negative change, the interval is 
shortened back to 4 weeks. 
 
Retreatment criteria: 
 
o According to this protocol VA stability means BCVA ≥ 84 letters (approximate 
Snellen equivalent of 20/20) or OCT <300 microns in the last 2 consecutive visits 
or no improvement can be achieved according to the investigators evaluation 
regarding VA and OCT measures in the last 2 visits . Stable patients do not require 
reinjection and should be evaluated in the next visit for reinjection. 
 
o If VA decreases ≥ 5 letters compared to previous visit and OCT is >300 microns, 
patients will be retreated. 
 
o If VA decreases ≥5 letters compared to the previous visit or CRT increases >50 
microns compared to the previous visit, patients will be retreated. 
 
o After 3 monthly injections of the investigational drug laser photocoagulation can 
be administered if VA worsens ≥10 letters and/or CRT increases >100 microns. 


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Figure 3-1 
Study design 
 
 
Study Design For Labelled Regime Arm 
 
 
Phase 
Screening 
Main Treatment 
Visit 
1 
2 
3 
4 
5 
6 -14 
Month 
0 
1 
2 
3 
4 – 12 
Day 
–7 to –1 
B 
30 
60 
90 
120 – 360 
Study Design For Wait and Extend Arm 
 
 
Phase 
Screening 
Main Treatment 
Visit 
1 
2 
3 
4 
5 
Visit number 
may vary 
acoording to 
the response 
of the patient 
Month 
0 
1 
2 
3 
4 – 12 
Day 
–7 to –1 
B 
30 
60 
90 
120 – 360 
 
 
 
 
3.2 
Rationale of study design 
A “wait and extend” regimen has been demonstrated efficient for treatment of wAMD in 
SALUTE study as mentioned above and found to be safe and tolerable. The rationale of this 
pilot study is to show that similar approach is applicable in treatment of DME. 
 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dose, dose regimen, titration scheme and tapering-off scheme, etc. are in accordance with 
product labeling in Arm 1. Since a “wait and extend” regimen has been demonstrated efficient 
for treatment of wAMD in SALUTE study and found to be safe and tolerable, it was decided 
to show the similar approach for the treatment of DME. 
 
3.4 
Purpose and timing of interim analyses/design adaptations 
There will be no interim analysis. 


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3.5 
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the inclusion/exclusion 
criteria, close clinical monitoring, since the study has been designed in a similar approach to a 
newly completed study which was completed with no major safety and tolerability concerns 
there are no unknown risks to Ranibizumab which may be serious and unforeseen. 
 
4 
Population 
The study population will consist of male and female patients (over 18 years old) admitted to 
hospital with Type 1 or Type 2 diabetes mellitus (according to ADA or WHO guidelines) with 
HbA1c not more than 12.0% at screening (Visit 1). Patients should be on diet, exercise, and/or 
pharmacological treatment for diabetes and should have a visual impairment due to focal or 
diffuse macular edema with center involvement in at least one eye, as demonstrated with color 
fundus photography, fluorescein angiography and OCT within 28 days of the baseline 
treatment. It is aimed to randomize a total of 86 patients in approximately 12 centers in 
Turkey. Since a 20% screening failure rate is expected, 104 patients have to be screened. 
 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male or female patients >18 years of age who have signed an informed consent 
3. Patients with Type 1 or Type 2 diabetes mellitus (according to ADA or WHO 
guidelines) with HbA1c not more than 12.0% at screening (Visit 1). Patients should be 
on diet, exercise, and/or pharmacological treatment for diabetes. 
4. Patients with visual impairment due to focal or diffuse macular edema with center 
involvement in at least one eye, as demonstrated with color fundus photography, 
fluorescein angiography and OCT within 28 days of the baseline treatment. If both 
eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be 
selected for study treatment unless, based on medical reasons, the investigator deems 
the other eye the more appropriate candidate for study treatment. The study eye must 
fulfill the following criteria at Visit 1: 
• BCVA score between 78 and 39 letters, inclusively, using ETDRS-like visual 
acuity testing charts at a testing distance of 4 meters (approximate Snellen 
equivalent of 20/32 to 20/160) 
• Decrease in vision is due to DME and not due to other causes, in the opinion of 
the investigator 


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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. 
 
1. Concomitant conditions in the study eye according to defined criteria such as 
infection, inflammation, uncontrolled glaucoma 
2. Active proliferative diabetic retinopathy or evidence of vitreomacular traction. in the 
study eye 
3. 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 
4. The history of vitrectomy in the study eye. 
5. Concomitant systemic condition according to defined criteria, eg. history of stroke, 
uncontrolled diabetes, renal failure, unsatisfactory controlled hypertension 
6. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days 
until the expected PD effect has returned to baseline, whichever is longer. 
7. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes. 
8. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
9. 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 laboratory test. 
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. Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
 
5 
Treatment 
5.1 
Protocol requested treatment 
 
5.1.1       Investigational treatment 
 
The investigational drug in this study will be ranibizumab 0.5 mg. 
 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile glass vial. Each 


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vial contains ranibizumab in an aqueous solution (pH 5.5) with histidine, trehalose, and 
polysorbate 20. The vial contains no preservative and is suitable for single use only. 
Ranibizumab must be stored according to the label instructions and it must be kept in a secure 
locked facility. The vials must be kept away from direct sunshine and must be kept in a 
refrigerator between 2°C -8°C (36°F – 46°F) and must not be FREEZED. 
No additional treatment beyond investigational treatment is requested for this trial. 
 
 
5.2 
Treatment arms 
Patients will be assigned to one of the following “2” treatment arms randomly 
A  study-specific  randomization  scheme  will  be  prepared  by the  CRO  to  follow  up  the 
randomization. 
• Arm 1 - Labeled regime arm: Treatment will be given monthly and continued until 
maximum visual acuity is achieved (the patient’s visual acuity is stable for three 
consecutive monthly assessments performed while on ranibizumab treatment). Thereafter 
patients should be monitored monthly for visual acuity. 
 
Treatment is resumed when monitoring indicates loss of visual acuity due to DME. 
Monthly injections should then be administered until stable visual acuity is reached again 
for three consecutive monthly assessments (implying a minimum of two injections). The 
interval between two doses should not be shorter than 1 month. 
 
• Arm 2 - Wait and Extend regime arm: Lucentis (ranibizumab) 0.5 mg will be injected 
subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will 
be called for control 1 month later. If the visual acuity has reached a stable level and there 
is no sign of edema on OCT, patients will not receive intravitreal injection and will be 
called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum 
of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal 
thickness and clinical findings. If there is a negative change, the interval is shortened back 
to 4 weeks. 
 
5.3 
Treatment assignment, randomization 
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 investigator will enter the 
randomization arm on the CRF. Randomization will be performed in 1:1 ratio. 
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 the CRO via a special 
randomization scheme prepared study specific for this study. 
 
5.4 
Treatment blinding 
The study is an open label study so there are no blinding procedures applicable. 


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5.5 
Treating the patient 
 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank CRF book. If an enrolled patient fails to be 
randomized or treated for any reason, the reason will be entered on the related page of the 
CRF. 
 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to the treatment arms, according to the 
confidential randomization list. Immediately before dispensing investigational treatment to the 
patient, investigator staff will detach the outer part of the label from the packaging and affix it 
to the source document (Drug Label Form) for that patient’s unique patient number. 
 
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. 
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 except for the randomization number. 
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. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator 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. 


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5.5.4 
Instructions for prescribing and taking study treatment 
All dosages prescribed and dispensed to the patient should be tracked in the related section of 
the CRF in each visit. 
The investigator should promote compliance and the importance of the attendance to the study 
visits by instructing the patient to attend the study visits since the injections will be followed 
up during the study visits and by stating that compliance is necessary for the patient’s safety 
and the validity of the study. 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Dose interruptions are permitted to achieve patient compliance and study completion. There 
are some guidelines that shows the below interruptions are suitable or not. 
The guidelines showing the interruptions are suitable or not 
Event 
Dose interruption criteria 
Intraocular Inflammation 
Discontinue the medication if intraocular inflammation is ≥2+ Study treatment 
will be allowed when intraocular inflammation returns to baseline or a better 
level. 
Loss of Visual Acuity 
Discontinue the medication if BCVA is decreased ≥30 letters compared to the 
baseline values as a result of the study treatment. Study treatment will be 
allowed when the change in BCVA returns back to ≤10 letters below the final 
BCVA assessment at the final injection before interruption of the medication. 
Intraocular Pressure (IOP) 
Discontinue the medication if IOP ≥30 mmHg in the study eye. Study 
treatment will be allowed when the IOP assessed by the investigator returns 
back to <30 mmHg level with treatment or spontaneously. 
Vitreous Hemorrhage 
Discontinue the medication if there is ≥2+ vitreous hemorrhage and ≥30 letters 
decrease in BCVA compared to Baseline. 
Rhegmatogen Retinal Tears or 
Detachment 
Discontinue the medication if there is retinal tear or detachment. The patient 
with grade 3 or 4 macular holes will not continue to the study treatment. 
Intraretinal Hemorrhage 
Discontinue the medication if there is intraretinal hemorrhage affecting the 
fovea and the size of the hemorrhage is equal to the 50% or more than the total 
lesion or ≥1 disc area. 
Local or Systemic Infection 
Discontinue the medication if one of the below occurs: If either of the two eye 
has infectious conjunctivitis, keratitis, scleritis or if the patient receives active 
treatment for a systemic infection. 
Intraocular Surgery 
Discontinue  the  medication  if  there  is  an  intraocular  surgical  intervention 
during the last 30 days. 
Grade 2 Target Adverse Events 
Discontinue the medication until the event returns back to Grade 1 or a better 
level. 
 
 
These changes must be recorded on the Dosage Administration Record CRF. 
 
5.5.6 
Rescue medication 
After  3  monthly  injections  of  the  investigational  drug  laser  photocoagulation  can  be 
administered if VA worsens >10 letters and/or CRT increases >100 microns. 


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5.5.7 
Concomitant treatment 
Moxifloxacin (Vigamox®) drop will be administered to the injection eye after injection. 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. 
 
5.5.8 
Prohibited Treatment 
 
Any concomitant medications including prescription drugs or over-the-counter preparations 
used by a patient during the study and until the conclusion of the study participation (except 
for routine medications given for ocular procedures required by the protocol, i.e. fluorescein, 
dilating drops, topical antibiotic, topical anesthetic) must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF including start and stop dates and reason for 
use. 
Laser photocoagulation for DME is permitted only as rescue treatment according to 
predefined criteria and needs to be 
recorded on the Concomitant medications/Significant non-drug therapies CRF 
Use of the following treatments is NOT allowed after the start of the study: 
• Chronic concomitant therapy with topical ocular corticosteroids 
• Other intravitreal medication in the study eye 
• Systemic medications known to be toxic to the lens, retina or optic nerve, including 
Deferoxamine, Chloroquine/ hydroxychloroquine (Plaquenil), Tamoxifen, Phenothiazines 
and Ethambutol 
• Treatment with glitazones  during the study. 
• Any other investigational drug 
 
The below treatments will be prohibited 30 days before randomisation: verteporfin 
(Visudyne®), external beam radiation treatment, , submacular surgery or other surgical 
interventions for DME. 
The  below  treatments  will  be  prohibited  90  days  before  randomisation:  focal  laser 
photocoagulation treatment. 
The  below  treatments  will  be  prohibited  120  days  before  randomisation:  macular  laser 
photocoagulation treatment. 
During the study, below treatment will be permitted: Retrobulber anesthesia to prevent eye 
movements, metochloropamide or other treatments for preventing the nausea due to 
fluorescein injection and other routine treatments for glaucoma. The patient will also be 
provided an additional topical antimicrobial medication to use 3 days after the injection 
which will be used 4 times a day. 
If the investigator decided that the other eye (other that the study eye) has a DME lesion or 
has a new DME lesion occurred during the study which needs treatment, appropriate routine 
ranibizumab treatment will be applied by the investigator; however any data will not be 
collected for the other eye. The ranibizumab treatment applied to the other eye will be given 
by NOVARTIS. 


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If a patient needs cataract surgery, the surgery must not be performed at least 28 days after 
last study treatment. After that, the next injection of the study medication should at least be 
performed 28 days after the cataract surgery. The patients should give every effort to comply 
to their normal examinations even in the surgery period that they did not receive the 
medication. The study medication must not be started if post-operative complications such as 
uveitis, cyclitis are seen after the cataract surgery. 
 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug and 
routine medications given for ocular procedures required by the protocol) and significant 
nondrug therapies (including physical therapy and blood transfusions) administered after 
enrollment into this study must be recorded on the Concomitant medications/Significant 
nondrug therapies page of the CRF. 
 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 
 
Ranibizumab treatment must be discontinued if the investigator determines that continuing it 
would result in a significant safety risk for that patient. The following circumstances require 
study drug discontinuation: 
• Withdrawal of informed consent 
• 3 missed doses of the study medication 
• Pregnancy 
• Occurrence of the below adverse events: Any grade 3 target adverse event, Grade 3 retinal 
tear or detachment, Grade 3 vitreous hemorrhage that is not cured (decrease as 1+ or below 
level) until the next planned injection date 
• Any other protocol deviation that results in a significant risk to the patient’s safety. 
• Use of prohibited medication 
 
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, on balance, he/she thinks that continuation would 
be detrimental to the patient’s well-being. 
 
Patients who discontinue study drug should NOT be considered withdrawn from the study. 
The investigator should encourage the patient to continue the scheduled assessments of the 
final visit. 
 
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, or fail to return for visits, or 
become lost to follow up for any other reason. 
 
If premature withdrawal occurs for any reason, the investigator must determine the primary 
reason for a patient’s premature withdrawal from the study and record this information on the 
Study Completion CRF. 
 
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 


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show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. 
 
 
 
5.5.10 
Study completion and post-study treatment 
The patient will be accepted to complete the study on Month 12 and in visit 14 for Labelled 
Regime Arm, the visit number may vary according the response of the patient for Wait and 
Extend Arm. 
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. 
 
5.5.11 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated 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 
investigator will be responsible for informing HA and/or ECs of the early termination of the 
trial. 
 
6 
Visit schedule and assessments 
 
In the below table, all the required study assessments are shown and the visits for those 
assessments are shown with an “X” sign. The patients must be seen during their planned visit 
days with a ±7 days visit window. 
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 ranibizumab, including a final 
contact at the 30-day point. Documentation of attempts to contact the patient should be 
recorded in the source documentation. 


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Assessment 
/Procedure 
Phase 
Screening 
Main Treatment Visits / Control Visits 
Visit 
for 
Labeled 
Regime Arm 
* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit for Wait 
and Extend 
Arm* 
1 
2 
3 
4 
5 
The visit numbers may vary according to the response of the 
patient. 
Month 
0 
1 
2 
3 
4 
5 
5 
7 
8 
9 
10 
11 
12 
Day 
-7 
to  - 
1 
B 
(1) 
30 
60 
90 
120 
150 
180 
210 
240 
270 
300 
330 
360 
EoT 
Informed consent 
X 
Incl/Exclusion criteria 
X 
X 
Randomisation 
X 
Medical history 
X 
Vital signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab.  Parameters  (HbA1c  and 
blood glucose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Function Parameters 
( Urea, Creatinin, Albumin, Total 
Protein, Uric Acid) 
X 
X 
X 
Pregnancy test b 
X 
ECG (12-lead) 
X 
X 
Concomitant Medication 
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 
Treatment (injections) c 
X 
X 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Rescue Laser Treatment 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmologic examination e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus photography 
X 
X 
FFA 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tonometry f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VFQ-25 
Xi 
Xi 
X 
Study Completion 
X 
 
B=Baseline; EoT=End of the Trial; BCVA= Best Corrected Visual Acuity; VFQ-25=Visual Function Questionnaire 
a) Blood pressure and pulse will be measured after the injection of the study medication (if applicable) 
b) Urine pregnancy test will only be performed to WOCBP. Additional tests may be performed as a decision of the 
investigator. 
c) Site staff will contact with the patient via phone 1-3 days after the study medication injection to inquire if there is any loss 
of vision, eye ache, unnormal redness or occurrence of any new ocular symptom. Patients will visit the site for an 
unscheduled visit if needed. 
d) If the lesion is active, according to the Royal College of Ophthalmology 
e) Ophthalmologic examination: slit lamp and fundus examination will be performed before injection (if applicable) 
f) IOP measurement with tonomerty will be performed before injection and after 60 minutes of injection. 
g) FFA is mandatory at month 0 and 12 and will be performed according to the investigators’s desicion at the other visits. 
h) Rescue laser treatment will be performed after the first three injection and according to the criteria described in the protocol. 
i) VFQ-25 will be questioned in either of the first two screening visits. 


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6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, 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 epoch of the 
study will have all adverse events occurring after informed consent is signed recorded on 
the Adverse Event CRF. Adverse events will be tracked in the baseline visit (visit 2) at day 0. 
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 the informed consent 
signature. 
 
6.2 
Baseline characteristics 
The below information will be recorded during screening/ visit 1 
• Ocular medical history: primary diagnosis and all other ocular conditions 
 
In addition below data will be collected during Screening/Visit 1 and Baseline/Visit 2 but if 
all the assessments/examinations are performed during Screening/Visit 1, they should not be 
repeated in Baseline/Visit 2. In this case, only the VFQ-25 and injection data should be 
completed in the CRF: 
• Related  medical  history:  significant  medical  conditions  and  surgeries  start  dates  and 
current situation. 
• Concomitant 
medication/significant 
non 
drug 
treatments: 
all 
applied 
medication/treatments 
 
6.3 
Treatment exposure and compliance 
The patients will be accepted as full compliance if the injections are performed as planned. 
 
6.4 
Efficacy 
Efficacy will be evaluated per visual acuity measurements, fundus photographs, fluorescein 
angiography and optical coherence tomography. 
 
Visual Acuity 
Visual acuity (VA) will be evaluated for both eyes in all study visits, as best corrected visual 
acuity according to the protocol. VA measurements will be performed in a sitting posture with 
a scale like ETDRS, 4 meters away from the baseline test distance.. 
 
Color Fundus Photography and Fluorescein Angiography 
Fluorescein angiography and color fundus photography will be performed together in 
Screening/Visit 1 and month 12. Digital fluorescein angiograms will be used for evaluations 
and the investigators can use their standards while diagnosing the fluorescein angiography 


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results.  Florescein  Angiography  can  be  performed  in  other  visits   according  to  the 
investigator’s decision. 
 
Optical Coherence Tomography 
Optical Coherence Tomography (OCT), will be performed to both eyes during the control 
visits of all patients. OCT evaluations should be performed before the study injections. Those 
evaluations will be performed by the trained staff in each study site. The images should be 
recorded to the digital video discs. 
 
6.4.1 
Appropriateness of efficacy assessments 
Those efficacy assessments were based on the previous studies performed with Ranibizumab. 
In addition the visual acuity assessments, as well as the optical coherence tomography that 
will be performed in this study are standard for this indication. 
 
6.5 
Safety 
 
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs), ophthalmic examinations, laboratory parameters and vital 
signs. Information on adverse events (AEs) and serious adverse events (SAEs) will be 
collected at every visit. 
 
6.5.1 
Vital signs 
 
 
Vital signs include BP and pulse measurements. After the patient has been sitting for five 
minutes, with back supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an automated validated device, e.g. OMRON, 
with an appropriately sized cuff. The repeat sitting measurements will be made at 1 - 2 minute 
intervals and the mean of the three measurements will be used. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
Vital signs will be evaluated at each visit and will be evaluated after the study injections if 
applicable. 
 
6.5.2 
Body Mass Index 
Body Mass Index will be calculated using height in centimeters (cm) and body weight (to the 
nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) and will only be measured 
only in Screening/Visit 1. 
 
6.5.3 
Laboratory evaluations 
The routine laboratory assessments will be performed at all visits for clinical chemistry and 
for renal function parameters the assessments will be performed at Baseline/Visit 1, Month 
3/Visit 5 and Month 12/Visit 14. The specimens will be obtained for the following 
assessments: 


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6.5.3.1 
Clinical chemistry 
HbA1c, fasting blood glucose 
 
6.5.3.2 
Renal Function Parameters 
Urea, Creatinin, Albumin, Total Protein, Uric Acid 
 
6.5.4 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at Screening/Visit 1 and at the end of study or 
premature discontinuation visit. Interpretation of the tracing must be made by a qualified 
physician and documented on the ECG section of the CRF. Each ECG tracing should be 
labeled with the study and subject number, date, and kept in the source documents at the study 
site. Clinically significant abnormalities should also be recorded on the Medical 
History/Adverse event CRF page. Clinically significant findings must be discussed with the 
Novartis Medical Monitor prior to enrolling the patient in the study. 
 
6.5.5 
Pregnancy and assessments of fertility 
A urine pregnancy testing will be performed only at screening for the WOCBP. 
 
6.5.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
 
6.6 
Other assessments 
 
Standard Ophthalmological Examination 
In each study visit, a standard ophthalmological examination will be performed to both eyes 
by using a slit lamp for stereoscopic fundus biomicroscopy and indirect stereo 
ophthalmoscopy. If needed, the pupil will be dilated by eye drops (ex: tropicamide) 
 
Tonometry 
In each study visit, tonometry will be performed to measure the intraocular pressure. IOP will 
be measured before each injection and 60 minutes (±10 minutes). In any time during the 
study, if a significant increase in IOP (≥30 mm Hg) is seen in a patient, the patient should be 
followed closely according to the investigator’s decision and additional IOP evaluations should 
be performed. The patient will leave the study site, after 60 minutes if any safety problems 
are not seen. If any safety problems or a sudden toxicity occurs, the patient will stay at the 
study site and will be followed according to the investigator’s decision. 
 
6.6.1 
Resource utilization 
Not applicable for this study. 
 
6.6.2 
Health-related Quality of Life 
Visual Function Questionnaire – 25 (VFQ – 25), will be completed at the selected sites at 
visits Baseline/Visit 2, and 12. month. VFQ-25, is a questionnaire consists of 25 questions 
aiming to evaluate the general visual function of the patients. VFQ-25 will be applied by the 


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investigator. VFQ-25 scores will be calculated according to the related guidelines. (Mangione 
et al. 1998, 2001). 
 
6.6.3 
Pharmacokinetics 
Not applicable for this study. 
 
6.6.4 
Pharmacogenetics/pharmacogenomics 
Not applicable for this study. 
 
6.6.5 
Other biomarkers 
Not applicable for this study. 
 
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 providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
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, 
• 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 CTCAE grade 
If CTCAE grading does not exist for an adverse event, use 1=mild, 2=moderate, 3=severe, 
and 4=life-threatening. CTCAE Grade 5 (death) is not used, but is collected in other CRFs 
(Study Completion, Death/Survival). 


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• its relationship to the study treatment (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: 
• 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, the 
interventions required to treat it, and the outcome. 


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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) 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 last study visit 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. 
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  is collected and recorded on the paper Serious Adverse Event 
Report Form. The investigator must assess the relationship to study drug, complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours  to the 
local Novartis Drug Safety and Epidemiology Department.  The telephone and telefax number 
of the contact persons in the local department of Novartis Drug Safety are listed in the 
investigator folder provided to each site and is also listed below. 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 and sent by 
giving the original report date. 
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 Novartis study drug, a Novartis 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 drug that this 
SAE has been reported. 


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SAE Reporting to Ministry of Health and Ethical Committee 
 
Local Novartis Turkey Drug Safety Department will report all suspected unexpected serious 
adverse reactions (SUSARs) to Ministry of Health as per The Regulation on Clinical Trials 
and Guidance on the collection, verification and submission of Adverse Event/Reaction 
Reports Occurring During Clinical Trials of Medicinal Products and Biological Products. 
 
 
7.3 
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. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
Contact information for Novartis Drug Safety department: 
 
Tel: 
 
Novartis Drug Safety Fax: 
 
 
Novartis Drug Safety Mailbox: 
 
 
 
 
 
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 study treatment is being 


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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, electrocardiograms, 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. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs. 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 must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 3-part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. The CRFs are forwarded to the Medical Documents 
Reception Center of Novartis or CRO working on behalf of Novartis by field monitors or by 
the investigational site, with one copy being retained at the investigational site. Once the 
CRFs are received by Novartis or CRO working on behalf of Novartis, their receipt is recorded, 
the original copy is placed in Central Files, and the non-carbon-required copy is forwarded 
to the responsible Data Management staff for processing. 
 
 
8.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research Organization 
(CRO) staff following their own internal standard operating procedures that have been 
reviewed and approved by Novartis. 
Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Other errors or 
omissions are entered on Data Query Forms, which are returned to the investigational site for 
resolution. The signed original and resolved Data Query Forms are kept with the CRFs at the 
investigator site, and a copy is sent to Novartis so the resolutions can be entered into the 
database. Quality control audits of all key safety and efficacy data in the database are made 
prior to locking the database. 
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 and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 


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8.4 
Data Monitoring Committee 
Not required. 
 
8.5 
Adjudication Committee 
Not required. 
 
9 
Data analysis 
 
 
9.1 
Analysis sets 
 
The Safety population will consist of all patients who received at least one intravitreal 
injection of ranibizumab. 
 
All analyses will be performed using the Safety population 
 
 
9.2 
Patient demographics and other baseline characteristics 
Descriptive statistics for continuous variables (i.e.: N, mean, standard deviation, median, 
maximum and minimum) and frequency and percent ranges for categorical variables will be 
given. Demographic data of the patients (including height and weight) and baseline visual 
acuity will be submitted as summary tables. Medical history and ocular medical history will 
be summarized per treatment arms. 
 
9.3 
Treatments 
Descriptive statistics will be given for application of the study medication. To evaluate the 
dosage compliance, the percent range of the patient that accepted fully complied will be 
given. Concomitant medication/significant non-drug treatments will be summarized as 
numbers and per cents. 
 
9.4 
Analysis of the primary and key secondary variable(s) 
 
9.4.1 
Variable(s) 
Mean change in Best-corrected visual acuity (BCVA) with ETDRS-like chart at a starting 
distance of 4 meters, at 12th month from baseline 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
There is no special hypothesis intended for this study. 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
Close monitoring of the study sites will be planned to prevent any missing data and any early 
drop outs due to lost to follow up of the patients. 


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9.4.4 
Supportive analyses 
Not applicable. 
 
9.5 
Analysis of secondary variables 
 
9.5.1 
Efficacy variables 
• Mean change in CRT (µm) by Optical coherence tomography at 12th month from baseline 
 
• Mean no. of injections over a 12-month treatment period 
 
• Mean no. of visits over a 12-month treatment period 
 
• Proportion of patients who gained ≥0, ≥5, ≥10 and ≥15 letters in BCVA at 12th month 
 
• Incidence of adverse events (AEs) and serious AEs (SAEs), by ophthalmic examinations 
and IOP measurements, and by changes in vital signs and laboratory parameters over the 
12-month assessment period. 
 
• Mean change in VFQ25 scores at 12th month from baseline 
 
9.5.2 
Safety variables 
All safety evaluations will be summarized and submitted for each visit per treatment arm. 
All adverse events will be summarized per treatment arm, as patient numbers and per cents for 
any adverse event experience and adverse events for each system organ class will be 
summarized. All information collected (i.e.: severity or grade or causality assessment) will be 
summarized. Deaths and SAEs requiring early discontinuation will be summarized separately. 
Laboratory details will be submitted as the descriptive statistics of the core data and for 
changes in the baseline data for each treatment arm (mean, median, standard deviation, 
interval) will be analyzed by highlighting the clinically notable changes. 
Vital signs will be summarized and descriptive statistics will be given for heart rate and pulse 
in a sitting posture including the baseline changes. 
 
9.5.3 
Resource utilization 
Not Applicable 
 
9.5.4 
Health-related Quality of Life 
Quality of Life variables will include the total score and sub-scores of the Visual Function 
Questionnaire – 25 (VFQ – 25) Descriptive statistics will be given including the changes 
according to the baseline. 
 
9.5.5 
Pharmacokinetics 
Not Applicable 


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9.5.6 
Pharmacogenetics/pharmacogenomics 
Not Applicable 
 
9.5.7 
Biomarkers 
Not Applicable 
 
9.5.8 
PK/PD 
Not Applicable 
 
9.6 
Interim analyses 
NA 
 
9.7 
Sample size calculation 
A sample size of 86 (43 for each treatment arm) can achieve 90% power to detect non- 
inferiority limit of 5 letter between treatment arm when significance level of the test is 0.025 
and the mean (standard deviation) letter change of labeled regime arm will be around 7 (7). 
To eliminate the effects of incomplete data which are expected in 1 year follow-up period, a 
priori 20% of drop-out rate is accepted; therefore at least 104 patients (52 for each treatment 
arm) will be included to the study. 
 
 
 
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), HA/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 
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 a proposed informed consent 
form  that  complies  with  the  ICH  GCP  guideline  and  regulatory  requirements  and  is 


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considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the HA/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after HA/IEC approval. 
Women of child bearing potential should be informed that taking the 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. 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 HA/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (HA/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the HA/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, HA/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 
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 HA/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 


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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 HA/IEC. Only 
amendments that are required for patient safety may be implemented prior to HA/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 HA/IEC at the study site should be informed within 
10 working days or less, if required by local regulations. 
 
12 
References 
References are available upon request 

SAP_000.pdf: 
SALUTE-D 
Statistical Analysis Plan 
Version 2.0 
NOVARTIS 
 
 
CONFIDENTIAL 
Page 1/13 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 2.0 
 
 
 
RANDOMIZED, OPEN-LABEL, NON-INFERIORITY STUDY COMPARING THE 
SAFETY AND EFFICACY OF WAIT AND EXTENT REGIMEN WITH THE 
APPROVED TREATMENT REGIMEN OF LUCENTIS (RANIBIZUMAB) IN 
TURKISH PATIENTS WITH VISUAL IMPAIRMENT DUE TO DIABETIC 
MACULAR EDEMA 
 
 
 
 
STUDY NUMBER: RFB002/Ranibizumab  
STUDY NAME: SALUTE-D  
 
 
 


SALUTE-D 
Statistical Analysis Plan 
Version 2.0 
NOVARTIS 
CONFIDENTIAL 
Page 2/13 
Statistical Analysis Plan Signature Page 
Version 2.0  
Sponsor 
Protocol 
Study title 
: 
NOVARTIS 
: 
[CRFB002DTR01] / NCT02262260
: 
Randomized, Open-Label, Non-Inferiority Study Comparing the 
Safety and Efficacy of Wait and Extent Regimen with the 
Approved Treatment Regimen of Lucentis (Ranibizumab) in 
Turkish Patients with Visual Impairment due to Diabetic Macular 
Edema 
, Bio., M.Sc. 
12.02.2018 
Author 
Date 
Reviewed by 
Date 
Approved by 
Date 


SALUTE-D 
Statistical Analysis Plan 
Version 2.0 
NOVARTIS 
 
 
CONFIDENTIAL 
Page 3/13 
 
 
TABLE OF CONTENTS 
    
1 
ABBREVIATIONS ...................................................................................................................................................... 5 
2 
BACKGROUND ........................................................................................................................................................... 6 
3 
OBJECTIVES OF THE STUDY ................................................................................................................................ 6 
3.1. 
PRIMARY OBJECTIVE ......................................................................................................................................... 6 
3.2. 
SECONDARY OBJECTIVES ................................................................................................................................ 6 
4 
STUDY DESIGN .......................................................................................................................................................... 7 
5 
ANALYZED POPULATIONS ................................................................................................................................... 8 
5.1. 
SAMPLE SIZE CALCULATION.......................................................................................................................... 8 
6 
ANALYSIS PLAN ........................................................................................................................................................ 9 
6.1 
DEMOGRAPHICS ............................................................................................................................................. 9 
6.2 
STUDY EYE ........................................................................................................................................................ 9 
6.3 
MEDICAL HISTORY ........................................................................................................................................ 9 
6.4 
VITAL FINDINGS ............................................................................................................................................. 9 
6.5 
LABORATORY TESTS ................................................................................................................................. 10 
6.6 
ASSESSMENT OF RENAL FUNCTION ................................................................................................... 10 
6.7 
ECG RESULTS................................................................................................................................................. 10 
6.8 
GENERAL OPHTHALMOLOGIC EXAMINATION .............................................................................. 10 
6.8.1 
Biomicroscopic Evaluation............................................................................................................. 10 
6.9 
BCVA (BEST CORRECTED VISUAL ACUITY) – FROM 4 METERS WITH ETDRS ................. 11 
6.10 
INTRAOCULAR PRESSURE (IOP) EXAMINATIONS ........................................................................ 11 
6.11 
OPTICAL COHERENCE TOMOGRAPHY ............................................................................................... 11 
6.12 
FLUORESCEIN FUNDUS ANGIOGRAPHY (FFA) ............................................................................... 12 
6.13 
CONCOMITANT MEDICATIONS / TREATMENTS ........................................................................... 12 
6.14 
EFFICACY EVALUATION ........................................................................................................................... 12 
6.14.1 
Visual Acuity ......................................................................................................................................... 12 
6.14.2 
Optical Coherence Tomography .................................................................................................. 13 


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6.14.3 
Injection and Visits ............................................................................................................................ 13 
6.14.4 
VFQ-25 Questionnaire Evaluation .............................................................................................. 13 
6.15 
SAFETY ASSESSMENT................................................................................................................................ 13 
6.15.1 
Adverse / Serious Adverse Events .............................................................................................. 13 
 
 
 


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1 
ABBREVIATIONS 
DME 
Diabetic Macular Edema 
BCVA 
Best Corrected Visual Acuity 
ECG 
Electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FFA 
Fundus Fluorescein Angiography 
OCT 
Optical Coherence Tomography 
SAE 
Serious Adverse Event 
CRT 
Central Retinal Thickness 
VFQ-25 
Visual Function Questionnaire 
 
 


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2 
BACKGROUND 
The purpose of this statistical plan is to define the tables, lists, data summaries and graphs to be 
prepared and to determine the statistical methods to be used for the analysis of the results of the 
study titled, “Randomized, Open-Label, Non-Inferiority Study Comparing the Safety and 
Efficacy of Wait and Extent Regimen with the Approved Treatment Regimen of Lucentis 
(Ranibizumab) in Turkish Patients with Visual Impairment due to Diabetic Macular Edema”. 
This statistical analysis plan has been prepared in pursuant to and in line with ICH-GCP 
principles and protocol no. IMM – 11 – 0003.   
3 
OBJECTIVES OF THE STUDY 
3.1. PRIMARY OBJECTIVE 
The primary objective of this study is to demonstrate that the “wait and extend” regimen of 
ranibizumab is non-inferior to the posology described in the prescribing information regarding 
the mean change in BCVA from baseline at month 12 in Turkish patients with vision loss due 
to diabetic macular edema.  
3.2. SECONDARY OBJECTIVES  
• To compare the mean change in CRT from baseline at month 12 between the two groups 
using OCT  
• To evaluate the number of injections required for a treatment period of 12 months with 
a “wait and extend” dosing regimen 
• To evaluate the number of visits required for a treatment period of 12 months with a 
“wait and extend” dosing regimen  
• To evaluate the number of patients with improvement in BCVA from baseline 
• To evaluate the number of patients with improvement of 5 or more letters from baseline  
• To evaluate the number of patients with improvement of 10 or more letters from baseline 
• To evaluate the number of patients with improvement of 15 or more letters from baseline 
• To evaluate the safety of intravitreal Lucentis (ranibizumab) injections in patients with 
DME  
• To describe patient-reported change in functional ability in patients treated with 
Lucentis  
 


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4 
STUDY DESIGN 
Study Design for the Prescribing Information Regimen Arm  
 
Phase 
Screening 
Main Treatment 
Visit 
1 
2 
3 
4 
5 
6 -14 
Month 
0 
1 
2 
3 
4 – 12 
Day 
–7 to –1  
B 
30 
60 
90 
120 – 360 
 
Study Design for the Wait and Extend Regimen Arm  
 
Phase 
Screening 
Main Treatment 
Visit 
1 
2 
3 
4 
5 
Number 
of visits 
may vary 
by patient 
response  
Month 
0 
1 
2 
3 
4 – 12 
Day 
–7 to –1  
B 
30 
60 
90 
120 – 360 
 
This is a randomized, controlled, multicenter, 12-month study concerning Lucentis 
(ranibizumab). Patients who provide consents will enter a screening period and their eligibility 
for enrollment will be evaluated. Following the screening period and evaluation of patient 
eligibility, only one eye will be selected / treated as the study eye. Once eligibility is confirmed, 
patients will be randomized to one of the following treatment arms: 
 
Arm 1: Prescribing information regimen arm: Treatment will be given monthly and maintained 
until maximum visual acuity is achieved (patient’s visual acuity remaining stable for three 
consecutive monthly assessments performed during ranibizumab treatment). Thereafter, 
patients will be followed-up monthly for visual acuity. 
 


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Treatment will be reinitiated in case a loss in visual acuity due to DME is determined during 
follow-up. Thereafter, monthly injections are to be performed until stable visual acuity is 
achieved for three consecutive monthly assessments (refers to at least two injections). The 
period between two doses should not be shorter than 1 month. 
 
Arm 2: Wait and extend regimen arm: Lucentis (ranibizumab) 0.5 mg will be injected at 
baseline, and at months 1 and 2. Following the three loading doses at baseline, patients will be 
invited for a follow-up visit one month later. Once visual acuity becomes stable and OCT 
demonstrates no evidence of edema, patients will no longer be given intravitreal injections and 
they will be invited to return 6 weeks later. The interval will be extended by 2 weeks for a 
maximum of 8 weeks for as long as the patient exhibits stable visual acuity, central retinal 
thickness and clinical findings. In the event of a negative change, the interval will be reduced 
back to 4 weeks. 
5 
ANALYZED POPULATIONS 
The study population will include male and female patients (above 18 years of age) who were 
admitted with Type 1 or Type 2 diabetes mellitus (according to ADA or WHO guidelines) with 
HbA1c values not exceeding 12.0% at screening (Visit 1). Patients should be following a diet, 
exercise and/or pharmacologic therapy for diabetes mellitus and should have vision loss for 
focal or diffuse macular edema with central involvement in at least one eye as demonstrated by 
color fundus photography, fluorescein angiography and OCT over a period of 28 days prior to 
initial treatment. A total of 86 patients from 12 centers in Turkey are expected to be randomized. 
Because a screening failure rate of 20% is anticipated, 104 patients will be needed to be 
screened.  
5.1.   SAMPLE SIZE CALCULATION 
A sample size of 86 patients (43 patients in each treatment arm) will provide 90% power to 
determine a non-inferiority margin of 5 letters between the treatment arms with a significance 
level of 0.025 for the test, and the mean (standard deviation) letter change of the prescribing 
information regimen arm will be approximately 7 (7). A 20% discontinuation rate is initially 
assumed in order to account for the missing data expected for a follow-up period of 1 year; thus, 
at least 104 patients (52 patients in each treatment arm) will be included in the study. 


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6 
ANALYSIS PLAN 
The number of attendance of the patients in each treatment group to visits and the total number 
of patients will be expressed as n and % in the table that should be available in the very 
beginning of the analysis.   
6.1 
DEMOGRAPHICS 
• Patients gender data: Patients, male and female, in both treatment regimens will be 
expressed separately as n and %.  
• Patients age: Patient age data for patients in the “Approved treatment regimen” and in the 
“Wait and extend treatment regimen” arms will be tabulated by calculating n, mean, 
standard deviation, minimum, maximum, median and 95% confidence interval.   
Patients will be grouped by age as 18-64 years, 65-84 years and ≥85 years, and patients in 
each age group will be listed as n and %. 
6.2 
STUDY EYE 
Study eyes (Right Eye or Left Eye) of the patients randomized to either of the two treatment 
regimens will be listed as n and %. 
6.3 
MEDICAL HISTORY 
Medical history before the written informed consent date and current medical conditions not 
related with the studied indication will be listed together with as n and % values.  
6.4 
VITAL FINDINGS 
Patients’ height (cm) and weight (kg) measurements will be tabulated providing descriptive 
statistics (n, mean, standard deviation, minimum, median, maximum and 95% confidence 
interval). Body Mass Index will also be calculated from height and weight variables using the 
Height /(Weight)2 formula, and will be described again using descriptive statistics. 
Systolic and Diastolic Blood Pressure (mm/Hg) measurements taken in the sitting position will 
be listed together with descriptive statistics. 
These evaluations will be performed for 14 visits for the patient group receiving the “Approved 
Treatment Regimen” and for all visits to which the patients attend for the group receiving the 
“Wait and Extend” treatment regimen.  
 


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6.5 
LABORATORY TESTS 
Patients’ HbA1C and Fasting Blood Glucose values will be listed for 14 visits for the patient 
group receiving the “Approved Treatment Regimen” and for all visits to which the patients 
attend for the group receiving the “Wait and Extend” treatment regimen, together with the 
descriptive statistics (n, mean, standard deviation, minimum, median, maximum and 95% 
confidence interval). 
6.6 
ASSESSMENT OF RENAL FUNCTION 
Patients’ Urea, Creatinine, Albumin, Total Protein and Uric Acid values will be collected at the 
first and fifth visits for patient groups receiving the “Approved Treatment Regimen” and “Wait 
and Extend” treatment regimen, and will be listed together with the descriptive statistics (n, 
mean, standard deviation, minimum, median, maximum and 95% confidence interval) for both 
visits for both treatment regimens.  
6.7 
ECG RESULTS 
For both treatment groups, the number and percentage (n and %) of patients with normal and 
abnormal ECG results will be tabulated. 
6.8 
GENERAL OPHTHALMOLOGIC EXAMINATION 
6.8.1 Biomicroscopic Evaluation 
Frequency and percentage values for the right and left eyes evaluated using biomicroscopy will 
be listed for 14 visits for the patient group receiving the “Approved Treatment Regimen” and 
for all available visits for the patient group receiving the “Wait and Extend” treatment regimen. 
Lids, conjunctiva, cornea, iris, lens, anterior chamber and other assessments will be presented 
as percentage and frequency values for normal and abnormal assessments for both treatment 
arms and for both visits. 
Frequency and percentage values for the right and left eyes evaluated using ophthalmoscopy 
will be listed for 14 visits for the patient group receiving the “Approved Treatment Regimen” 
and for all available visits for the patient group receiving the “Wait and Extend” treatment 
regimen. 
The list of abnormalities identified with color fundus photography will be provided. 


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6.9 
BCVA (BEST CORRECTED VISUAL ACUITY) – FROM 4 METERS WITH 
ETDRS 
Descriptive statistics (n, mean, standard deviation, minimum, median, maximum and 95% 
confidence interval) for BCVA Test scores applied to both eyes will be tabulated for all 14 
visits for the patient group receiving the “Approved Treatment Regimen” and until the last 
available visit for the patient group receiving the “Wait and Extend” treatment regimen. For 
both treatment groups, the change between the first and final visits will be compared using the 
t-test for paired sequences or Wilcoxon Signed Rank Test based on the fit of the data to normal 
distribution. 
6.10 INTRAOCULAR PRESSURE (IOP) EXAMINATIONS 
Descriptive statistics (n, mean, standard deviation, minimum, median, maximum and 95% 
confidence interval) for Intraocular Pressure values will be collected for all 14 visits for the 
patient group receiving the “Approved Treatment Regimen” and until the last available visit for 
the patient group receiving the “Wait and Extend” treatment regimen. 
6.11 OPTICAL COHERENCE TOMOGRAPHY  
The device used for OCT will be listed together with n and % values for both treatment arms. 
Frequency (n) and percentage (%) values for the options describing the results of intraretinal 
edema involving the macula (Yes, No, Not evaluated) will be tabulated for both groups. Type 
of the edema, if applicable, will also be tabulated using frequency and % values. 
Descriptive statistics (n, mean, standard deviation, minimum, median, maximum and 95% 
confidence interval) for central thickness values for both eyes will be listed separately for each 
of the treatment arms. 
Frequency (n) and percentage (%) values for the options describing subretinal fluid results (Yes, 
No, Suspected, Not evaluated) and the options describing results of vitreoretinal interface 
changes (Yes, No) will be tabulated for both eyes. Frequency (n) and percentage (%) values for 
the options, i.e. vitreoretinal traction, epiretinal membrane and macular hole will also be listed 
for patients with vitreoretinal interface changes. 
 


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6.12 FLUORESCEIN FUNDUS ANGIOGRAPHY (FFA) 
For the results of FFA performed compulsorily at the first and month 12 visits and at 
investigator discretion during other visits, answers describing presence of diabetic macular 
edema (Yes, No) will be individually listed as frequency (n) and percentage (%) values for the 
right and left eyes in each of the treatment arms, and frequency (n) and percentage (%) values 
for the specified “Focal” and “Diffuse” options will be listed for those with the “Yes” answer.  
Yes and No answers to macular ischemia and peripheral ischemia questions will be individually 
listed as frequency (n) and percentage (%) values for the right and left eyes in each of the 
treatment arms. For Yes, No and Suspected answers to another condition identified with FFA, 
frequency (n) and percentage (%) values will be tabulated, and the details provided for the Yes 
answers will be provided.  
The rates of diabetic macular edema, macular ischemia, peripheral ischemia and other 
conditions identified with FFA will be compared during the first and month 12 visits using the 
Mc Nemar test. 
6.13 CONCOMITANT MEDICATIONS / TREATMENTS 
Yes or No answers to whether patients were receiving concomitant medications / treatments 
will be listed as frequency (n) and percentage (%) values for both treatment groups. 
The medications used by the patients receiving concomitant medications / treatments will be 
grouped and listed.  
6.14 EFFICACY EVALUATION 
6.14.1 Visual Acuity 
In order to demonstrate that the “wait and extend” regimen of ranibizumab is non-inferior to 
the posology described in the prescribing information, mean change in BCVA at month 12 from 
the baseline visit will be determined for both treatment groups, and a comparison will be made 
between the two groups using the Mann Whitney u test. 
The number of patients with improvement in BCVA from baseline will be compared for the 
two treatment groups using the Chi-Square test (with Fisher’s Exact Test where appropriate). 
The number of patients with improvement of 5 or more letters from baseline will be compared 
for the two treatment groups using the Chi-Square test (with Fisher’s Exact Test where 
appropriate). 


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The number of patients with improvement of 10 or more letters from baseline will be compared 
for the two treatment groups using the Chi-Square test (with Fisher’s Exact Test where 
appropriate). 
The number of patients with improvement of 15 or more letters from baseline will be compared 
for the two treatment groups using the Chi-Square test (with Fisher’s Exact Test where 
appropriate). 
6.14.2 Optical Coherence Tomography 
The mean change from baseline to month 12 in Central Retinal Thickness determined with 
Optical Coherence Tomography for both eyes will be calculated for both groups and will be 
compared using the Mann Whitney u test. 
6.14.3 Injection and Visits 
The number of injections and visits required for a treatment period of 12 months with a “wait 
and extend” dosing regimen will be evaluated. 
6.14.4 VFQ-25 Questionnaire Evaluation  
Scores from the VFQ-25 questionnaire determined at the first and month 12 visits will be 
compared separately in the “Approved treatment regimen” and “Wait and extend” treatment 
regimen groups using the Wilcoxon Signed Rank Test. 
6.15 SAFETY ASSESSMENT 
6.15.1 Adverse / Serious Adverse Events 
The list of the Adverse / Serious Adverse Events (SAE) reported in each visit will be provided. 
All adverse events will be examined regarding the visits they occurred, severity (mild, 
moderate, severe), relationship with the drug (suspected, not suspected), outcome (continuing, 
resolved), actions taken (no action taken, dose adjusted/dosing interrupted, additional treatment 
given, non-pharmacological treatment given, hospitalized), additional treatments if applicable, 
time between hospitalization and discharge dates, and length of hospital stay.