Clinical trial NCT02257632
Conditions: Wet Age-Related Macular Degeneration
Sponsor: Novartis Pharmaceuticals
Start date: 2015-04-08; Completion date: 2017-06-08
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to compare the effect of intravitreal injections of ranibizumab and aflibercept on systemic VEGF protein levels in treatment naïve wet neovascular Age-related Macular Degeneration (wAMD) patients in a detailed time course.

Detailed description:
A planned study visit schedule was established at the time of baseline visit (day 1) for all patients. Study assessments for patients were performed at screening visit, baseline (day 1), day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day 169 at biweekly visits.

Arms: arm 1: 6 monthly intravitreal injections of 0.5 mg ranibizumab arm 2: 3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab
Interventions: intervention 1: Ranibizumab 0.5 mg intervention 2: Aflibercept 2 mg
Intervention descriptions: intervention 1: Administered as an intravitreal injection intervention 2: Administered as an intravitreal injection

Protocol documents:
Prot_000.pdf: 
Novartis Pharma 
Confidential 
Page 1 
Clinical Study Protocol including Amendment 2 
Study No. CRFB002ADE27 
Version 02 (27.04.2015) 
Clinical Development 
RFB002 (Ranibizumab; Lucentis®) 
Protocol number (CRFB002ADE27 / NCT02257632) including 
Amendment 2 
A randomized, single-blinded, multicenter, phase IV study to 
compare systemic VEGF protein dynamics following monthly 
intravitreal injections of 0.5 mg ranibizumab versus 2 mg 
aflibercept until study week 12 in patients with neovascular (wet) 
age-related macular degeneration 
Acronym: TIDE AMD 
Author(s): 
 
Document type: 
Clinical Study Protocol including Amendment 2 
EUDRACT number : 
2014-001182-27 
Development phase: 
IV 
Version No. 
02 
Release date: 
27.04.2015 
Property of Novartis Pharma  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


Novartis Pharma 
Confidential 
Page 2 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Signature Pages for Amendment 2 
Compound name / number: Ranibizumab (Lucentis®)/ RFB002 
Protocol number: CRFB002ADE27 
Approved by the following 
Signatures of Novartis Personnel: 
 
 
 
  
 
signature  
 
date 
 
 
  
 
signature  
 
date 
 
 
 
 
signature  
 
date 
 


Novartis Pharma 
Confidential 
Page 3 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Signature of Coordinating Investigator for Amendment 2 
 
 
 
 
signature  
 
date 
 


Novartis Pharma 
Confidential 
Page 4 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Signature Page for Investigator for Amendment 2 
 
Compound name / number: Ranibizumab (Lucentis®)/ RFB002 
Protocol number: CRFB002ADE27 
 
I have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with the principles outlined in the 
Declaration of Helsinki. Note: Any deviations from this protocol require a formal 
amendment to be approved by the responsible ethics committee. 
 
 
Investigator 
 
 
Center name / location: 
 
signature  
 
date 
 
 
institution (where applicable) 
 
city 
 
 


Novartis Pharma 
Confidential 
Page 5 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 8 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Amendment 2 .................................................................................................................... 11 
Amendment 1 .................................................................................................................... 11 
1 
Background ........................................................................................................................ 13 
2 
Study purpose .................................................................................................................... 15 
3 
Objectives (and related endpoints) .................................................................................... 15 
3.1 
Primary objective(s) ............................................................................................... 15 
3.2 
Secondary objective(s) ........................................................................................... 15 
 
 16 
4 
Study design ...................................................................................................................... 16 
5 
Population .......................................................................................................................... 18 
5.1 
Inclusion/exclusion criteria .................................................................................... 18 
5.1.1 
Inclusion criteria .................................................................................... 18 
5.1.2 
Exclusion criteria .................................................................................. 18 
5.2 
Premature patient withdrawal ................................................................................ 21 
6 
Treatment ........................................................................................................................... 22 
6.1 
Patient numbering .................................................................................................. 22 
6.2 
Investigational drugs .............................................................................................. 22 
6.2.1 
Ranibizumab ......................................................................................... 22 
6.2.2 
Aflibercept ............................................................................................. 22 
6.3 
Treatment arms ...................................................................................................... 23 
6.4 
Treatment assignment ............................................................................................ 23 
6.5 
Treatment blinding ................................................................................................. 23 
6.6 
Treating the patient ................................................................................................ 24 
6.6.1 
Dispensing the study drug ..................................................................... 24 
6.6.2 
Instructions for use of study drug .......................................................... 24 
6.6.2.1 
Treatment group 1 ................................................................................. 24 
6.6.2.2 
Treatment group 2 ................................................................................. 24 
6.6.2.3 
Treatment of the fellow eye .................................................................. 24 
6.6.3 
Study drug supply and resupply, storage, and tracking ........................ 25 
6.6.4 
Study drug compliance and accountability ........................................... 25 


Novartis Pharma 
Confidential 
Page 6 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
6.6.5 
Disposal and destruction ....................................................................... 25 
6.6.6 
Permitted study drug dose adjustments and interruptions..................... 25 
6.6.7 
Rescue medication ................................................................................ 26 
6.6.8 
Other concomitant treatment ................................................................. 26 
6.6.9 
Study drug discontinuation ................................................................... 26 
6.6.10 
Emergency unblinding of treatment assignment ................................... 27 
6.6.11 
Study completion and post-study treatment .......................................... 27 
7 
Visit schedule and assessments ......................................................................................... 28 
7.1 
Information to be collected on screening failures .................................................. 31 
7.2 
Demographics/other baseline characteristics ......................................................... 31 
7.3 
Treatment exposure and compliance ..................................................................... 32 
7.4 
Efficacy .................................................................................................................. 32 
 
 32 
 
 33 
7.4.3 
Color Fundus Photography and Fluorescein Angiography ................... 33 
7.5 
Safety ..................................................................................................................... 34 
7.5.1 
Adverse events ...................................................................................... 34 
7.5.2 
Physical examination ............................................................................ 34 
7.5.3 
Vital signs.............................................................................................. 34 
7.5.4 
Laboratory evaluations .......................................................................... 34 
7.5.5 
Pregnancy test and assessments of fertility ........................................... 35 
7.5.6 
Eye-specific safety monitoring ............................................................. 35 
7.6 
Tolerability/acceptability ....................................................................................... 36 
7.7 
Resource utilization ............................................................................................... 36 
 
 36 
7.9 
Pharmacokinetics/pharmacodynamics ................................................................... 36 
7.9.1 
Pharmacodynamics ............................................................................... 36 
7.10 
Pharmacogenetics/pharmacogenomics .................................................................. 36 
 
 37 
8 
Safety monitoring .............................................................................................................. 38 
8.1 
Adverse events ....................................................................................................... 38 
8.1.1 
Adverse event definition and reporting ................................................. 38 
8.1.2 
Laboratory test abnormalities ................................................................ 38 
8.2 
Serious adverse events ........................................................................................... 39 
8.2.1 
Serious adverse event definition, treatment and follow-up ................... 39 


Novartis Pharma 
Confidential 
Page 7 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
8.2.2 
Serious adverse event reporting ............................................................ 40 
8.3 
Pregnancy reporting ............................................................................................... 41 
8.4 
Reporting of adverse events and pregnancies after the last dose of study drug 
taken ....................................................................................................................... 41 
8.5 
Data Monitoring Board .......................................................................................... 41 
9 
Data review and database management ............................................................................. 42 
9.1 
Site monitoring ...................................................................................................... 42 
9.2 
Data collection ....................................................................................................... 42 
9.3 
Database management and quality control ............................................................ 42 
10 Data analysis ...................................................................................................................... 43 
10.1 
Populations for analysis ......................................................................................... 43 
10.2 
Patient demographics/other baseline characteristics ............................................. 44 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 44 
10.3.1 
Investigational Treatment ...................................................................... 44 
10.3.2 
Concomitant therapies ........................................................................... 44 
10.4 
Analysis of the primary objective(s) ...................................................................... 45 
10.4.1 
Variable ................................................................................................. 45 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 45 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 45 
10.4.4 
Supportive analyses ............................................................................... 45 
10.5 
Analysis of secondary objectives ........................................................................... 46 
 
 46 
10.5.2 
Safety ..................................................................................................... 46 
10.5.3 
Tolerability ............................................................................................ 47 
10.5.4 
Pharmacokinetics/ pharmacodynamics ................................................. 47 
 
 47 
10.6 
Interim analysis ...................................................................................................... 48 
10.7 
Sample size calculation .......................................................................................... 48 
10.8 
Power for analysis of critical secondary variables ................................................ 49 
11 Discussion and rationale for study design features ........................................................... 49 
12 References ......................................................................................................................... 50 
Appendix 1: Ethical considerations and administrative procedures .................................. 53 
Appendix 2: Clinically notable laboratory values and vital signs ..................................... 55 
 


Novartis Pharma 
Confidential 
Page 8 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
List of tables 
Table 4-1 
Study outline ......................................................................................... 17 
Table 6-1 
Prohibited treatment .............................................................................. 26 
Table 7-1 
Assessment schedule for patients .......................................................... 29 
Table A2-1 
Critical values ........................................................................................ 55 
Table A2-2 
Criteria for the diagnosis of diabetes .................................................... 55 
 
List of abbreviations 
ADA 
American Diabetes Association 
AE 
adverse event 
AMD 
Age-related macular degeneration 
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
 
 
bpm 
Beats per minute 
BSL 
Baseline 
CF 
Color fundus photography 
CHMP 
Committee for Medicinal Products for Human Use 
CNV 
Choroidal neovascularization 
CRC 
Central reading center 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
 
  
DME 
Diabetic macular edema 
EMA 
European Medicines Agency 
EOS 
End of study 
EOT 
End of treatment 
 
 
EU 
European Union 
 
FA 
Fluorescein angiography 


Novartis Pharma 
Confidential 
Page 9 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
FAS 
Full analysis set 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
 
 
PPS 
Per-protocol Set  
RPE 
Retinal pigment epithelium 
RS 
Randomized Set 
RVO 
Retinal vein occlusion 
SAE 
serious adverse event 
SCN 
Screening 
 
 
SmPC 
Summary of product characteristics 
VA 
Visual acuity 
VAP 
Validation and Planning 
VEGF 
Vascular endothelial growth factor (-A) 
 
wAMD 
Neovascular (wet) age-related macular degeneration 
WHO 
World Health Organization 
 


Novartis Pharma 
Confidential 
Page 10 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
End of study visit 
Point/time at which the patient came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
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) 
  
 
 
 
 
Fellow eye 
The fellow eye is the non-study eye. 
Investigational drug 
The study drug whose properties are being tested in the study 
Patient number 
A number assigned to each patient who enrolls in the study; when 
combined with the center number, a unique identifier for each 
patient in the study is created. 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific study arm assignment 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug, combination of drugs 
and any control drugs including placebo 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Study eye 
The study eye is the eye selected by the investigator at baseline 
(according to the protocol) to receive the study treatment 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points 


Novartis Pharma 
Confidential 
Page 11 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Amendment 2 
The protocol has been amended to correct two exclusion criteria in the protocol and to correct an 
error in table 7-1 .  
At the time of the amendment, two patients have been randomized. 
 
Changes to the protocol 
 Exclusion criteria #4 was changed insofar that only patients with Type 1 or Type 2 
diabetes mellitus with glycosylated hemoglobin (HbA1c) > 10% (> 86 mmol/mol) at 
screening are excluded from the study. Rationale: A large proportion of nAMD 
patients suffer from adult-onset diabetes and should have the possibility to be included 
in the study.  
 Exclusion criteria #12: The clarification “…requiring treatment…” has been added. 
Rationale: Background for this exclusion criterion is that that the TIDE AMD study 
will investigate whether intravitreally injected anti-VEGF drugs have an effect on 
VEGF levels in the systemic circulation. An injection of the fellow eye should thus be 
avoided. Therefore not the medical condition of the fellow eye per se is excluded but 
the medical condition requiring treatment of the fellow eye with an anti-VEGF drug. 
 Table 7-1: The  ±1 day visit window of visit 3 was deleted. As written in chapter 7.9.1 
the blood sampling at visit 3 should be performed 24 h ± 2 h after blood sampling at 
visit 2.  
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described in 
this amendment require IRB/IEC and Health Authorities approval prior to implementation. 
 
 
Amendment 1 
The protocol has been amended to clarify and correct certain criteria and procedures in the 
protocol. 
At the time of the amendment, no patients had been screened for inclusion. 
 
Changes to the protocol 
 The allocation of Exclusion criteria #19 was changed from “For fellow eye” to “For 
either eye”. Rationale: The Inclusion criteria #4 states: “…newly diagnosed, untreated 
(…) CNV lesion…”, which indicates that the study eye must not have had a previous 
treatment with any anti-angiogenic drug. To clarify this further within the exclusion 
criteria, the exclusion criteria #19 was changed as stated above.  


Novartis Pharma 
Confidential 
Page 12 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 The description of Section 6.4 “Treatment assignment” was specified. 
 A descriptive subgroup analyses to explore gender differences for primary results was 
added to Section 10.4.4 “Supportive analyses”. 
 
The changes described in this amendment are non-substantial and require no Institutional 
Review Board (IRBs)/Independent Ethics Committee (IECs) and Health Authorities approval 
prior to implementation. 


Novartis Pharma 
Confidential 
Page 13 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
1 
Background 
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 
the age of 55 years in developed countries (Coleman 2008). Most cases of severe visual loss 
in AMD are patients with wet (neovascular) AMD (wAMD), which is characterized by 
choroidal neovascularization (CNV) (Dhoot & Kaiser 2012). Increased expression of vascular 
endothelial growth factor A (VEGF-A) in the retinal pigment epithelium (RPE) is associated 
with the development of CNV lesions (Ozkiris 2010; Kovach 2012).  
Intravitreal injection of a VEGF-A inhibitor is currently the standard treatment for 
neovascular AMD (Kovach 2012; Kaiser 2010).  
 
VEGF inhibitors used in ophthalmology 
i. 
Ranibizumab (Lucentis) is a humanized recombinant monoclonal antibody fragment 
targeted against VEGF-A. Ranibizumab was approved for use in wAMD in 2007 in 
the European Union (EU) (Lucentis EU Summary of Product Characteristics 
[SmPC]). 
ii. 
Aflibercept (Eylea®) is a recombinant fusion protein consisting of portions of human 
VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG. 
Aflibercept binds and inhibits VEGF-A, VEGF-B, Placental growth factor (PlGF)-1 
and -2 (Eylea® EU SmPC). Aflibercept was approved for use in wAMD in 2012 in the 
EU.  
iii. 
Bevacizumab (Avastin®) is a full-length antibody raised against VEGF-A. Despite 
being only approved for the treatment of metastatic tumors (Avastin® EU SmPC), 
bevacizumab is used off-label by ophthalmologists for the treatment of neovascular 
pathologies in the eye. 
In standard clinical practice, the treating ophthalmologist may change the drug or the 
treatment regimen if patients do not respond optimally to one of the previously mentioned 
anti-VEGF drugs or if intolerances or contraindications occur. Accordingly, patients may 
undergo one or several switches from one anti-VEGF drug to another during their therapy. 
The analysis of an american ophthalmologists’ claim database revealed that 25% of wAMD 
patients were switched from one anti-VEGF drug to another during their first year of therapy 
(Ferreira 2013).  
 
Systemic VEGF levels 
Although the injection of VEGF inhibitors used to treat wAMD is performed intravitreally, 
there are several lines of evidence showing that a small portion of the drugs may pass to the 
systemic circulation and have systemic effects (see below). 


Novartis Pharma 
Confidential 
Page 14 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
This may be explained by the molecular biology underlying this process: Trials in adult mice 
showed that intravitreally administered full-length immunoglobulin G (IgG) was transported 
across the blood-retinal barrier into the systemic circulation. So called neonatal Fc receptors 
expressed in the blood-retina barrier are known to perform an Fc-dependent IgG transport and 
protect against their catabolism, resulting in their long serum half-life as compared with other 
proteins (Kim 2009; Yeung 2010). Both aflibercept and bevacizumab comprise an Fc 
fragment which suggests that an Fc-dependent transport of these anti-VEGF inhibitors to the 
systemic circulation takes place. 
In contrast, ranibizumab represents an antibody Fab fragment only, which show greater retinal 
penetration and shorter systemic half-lifes than IgGs (Mordenti 1999). In addition, the 
absence of Fc eliminates the Fc-dependent transport across the blood-retina barrier, 
complement activation or cell-dependent cytotoxicity and thus results in a reduced systemic 
exposure than drugs comprising an Fc domain (Ferrara 2006; Raghavan & Bjorkman 2006). 
This was confirmed by studies in cancer which demonstrated that the systemic half-life of a 
Fab fragment is a few hours, whereas that of a full-length IgG is up to 3 weeks (Chong 2012; 
Reff 2002). 
Under physiological conditions the VEGF pathway is essential for processes such as 
angiogenesis, vasodilation, endothelial cell integrity and for the glomerular filtration barrier 
(Chen & Cleck 2009). VEGF signaling plays a critical role in the homeostasis of the adult 
vascular system and VEGF is essential for cardiovascular repair and regeneration (Cruess 
2013; Lee 2007). Inhibition of VEGF signaling can result in pathological consequences that 
include compromised wound healing and tissue repair, hypertension, arterial thromoembolic 
events, cardiac dysfunction, proteinuria or renal dysfunction (Chen & Cleck 2009). A 
sustained and significant reduction of systemic VEGF levels due to passage of intravitreally 
administered VEGF inhibitors may increase the risk for systemic side effects and thus should 
be avoided. 
Only few studies report systemic VEGF level measurements following intravitreal anti-VEGF 
injections of ranibizumab and bevacizumab. It was shown that intravitreal injections of the 
full-length anti-VEGF-A antibody bevacizumab, but not of the Fab fragment ranibizumab 
significantly decrease systemic VEGF-A levels in wAMD patients. Following bevacizumab 
injections, systemic VEGF-A levels are reduced by -74% at day 28, -42% at month 3, -69% at 
month 12 and -78% at month 24 compared to baseline. In contrast, intravitreal ranibizumab 
injections only resulted in VEGF-A inhibition of -16% at day 28, -1% at month 3, -20% at 
month 12 and -28% at month 24 compared to baseline (Carneiro 2012; Chakravarthy 2012; 
Harding 2013; Zehetner 2013). A pooled analysis of two large clinical trials showed a 
significantly increased risk of any systemic SAE for treatment with bevacizumab compared to 
ranibizumab in patients with wAMD (Chakravarty 2013).  
To date, only one study investigated the pharmacodynamic effect of aflibercept on systemic 
VEGF protein levels and reported a significant suppression of systemic VEGF levels after one 
intravitreal aflibercept injection of approx. -67% at day 7 and approx. -33% at day 28 
compared to baseline. In contrast, wAMD patients receiving one intravitreal ranibizumab 
injection showed a change from baseline VEGF plasma levels of approx. + 6% at day 7 and 
approx. +12% at day 28 (Avery 2013).  


Novartis Pharma 
Confidential 
Page 15 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Given that aflibercept features an Fc part, a similar transport mechanism for aflibercept over 
the blood-retina-border as for bevacizumab can be hypothesized. This assumption is in line 
with the aflibercept european public assessment report, which reports that almost 20% of 
intravitreally injected aflibercept passes to the systemic circulation. This was considered as an 
important potential risk in the aflibercept risk management plan (EMA CHMP assessment 
report on aflibercept, Procedure No. EMEA/H/C/002392/).  
 
2 
Study purpose 
The purpose of the study is to compare the effect of intravitreal injections of ranibizumab and 
aflibercept on systemic VEGF protein levels in treatment naïve wAMD patients in a detailed 
time course. 
The primary endpoint of this study is the area under the curve (AUC) of VEGF-A protein 
concentration in blood plasma between day 2 and study week 12. Both drugs will be 
administered as three monthly intravitreal injections.  
In the second part of the study from study week 12 to week 24 all patients will receive three 
monthly ranibizumab injections and systemic VEGF-A protein levels will be compared 
between the two study groups. In addition, the study aims to explore whether systemic VEGF 
levels of patients switching from aflibercept to ranibizumab will adjust to levels comparable 
to baseline or to levels comparable as in patients treated with ranibizumab from baseline.  
 
3 
Objectives (and related endpoints) 
3.1 
Primary objective(s) 
To compare systemic VEGF-A protein levels following monthly intravitreal injections of 0.5 
mg ranibizumab versus 2 mg aflibercept as measured by the area under the curve (AUC) from 
baseline to study week 12. 
 
3.2 
Secondary objective(s) 
To compare systemic VEGF-A protein levels in patients switching from monthly 2 mg 
aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with 
monthly 0.5 mg ranibizumab from baseline as measured by the AUC from study week 12 to 
week 24. 
To explore whether systemic VEGF-A levels of patients switching from aflibercept to 
ranibizumab will adjust to levels comparable to baseline or to levels comparable as in patients 
treated from baseline with ranibizumab from study week 12, over time up to week 24. 


Novartis Pharma 
Confidential 
Page 16 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
4 
Study design 
This is a randomized, single-blinded, multicenter, phase IV study to compare systemic VEGF-
A protein levels following monthly intravitreal injections of 0.5 mg ranibizumab versus 2 mg 
aflibercept until study week 12 in patients with wAMD. From week 12 on all patients will 
receive monthly intravitreal injections of 0.5 mg ranibizumab until study week 20 in order to 
compare systemic VEGF-A protein levels in patients switching from aflibercept to 


Novartis Pharma 
Confidential 
Page 17 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
ranibizumab injections with patients treated with ranibizumab only from study week 12 to 
week 24. A blinded central laboratory will evaluate systemic VEGF plasma levels. 
Patients with wAMD will be randomized in a 1:1 ratio to one of the following treatment 
groups:  
- 
Group 1: Six monthly intravitreal injections of 0.5 mg ranibizumab  
- 
Group 2: Three monthly intravitreal injections of 2 mg aflibercept followed by three 
monthly intravitreal injections of 0.5 mg ranibizumab  
The study requires 16 study visits during 24 weeks and the primary endpoint will assess data 
from baseline to study week 12.  
At visit 1 (to occur between day -14 and day -1), after signing the informed consent, patients 
are enrolled into the study and procedures to allow assessment of the study eligibility criteria 
are performed. At the baseline visit on day 1 (visit 2), patients whose eligibility is confirmed 
will be randomized into one of the treatment arms (group 1 or group 2).  
 
For an overview of the study design please see Figure 4-1 below: 
Table 4-1 
Study outline 
 
 
 
 


Novartis Pharma 
Confidential 
Page 18 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
5 
Population 
The study will include adult patients with active, newly diagnosed, untreated wAMD. A total 
of 40 patients (20 in each treatment arm) will be enrolled from approx. 7 centers across 
Germany. Patients will be treated in an outpatient setting.  
5.1 
Inclusion/exclusion criteria  
The investigator must ensure that all patients who meet the following inclusion and do not 
fulfill any of the exclusion criteria are offered enrollment in the study.  
5.1.1 
Inclusion criteria  
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
Inclusion criteria for patient 
1. Male or female patients, ≥ 18 years of age. 
2. Written informed consent must be obtained before any study-related assessment is 
performed. 
Inclusion criteria for study eye 
3. Visual impairment predominantly due to neovascular AMD. 
4. Active, newly diagnosed, untreated, angiographically documented, CNV lesion (i.e. 
leakage on fluorescein angiography plus intraretinal, subretinal or sub-RPE fluid on OCT) 
secondary to neovascular AMD in line with SmPC of ranibizumab (Lucentis®) and 
aflibercept (Eylea®). 
5.1.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusion parameters can be applied by the investigator, in order that the study 
population will be representative of all eligible patients. 
Exclusion criteria for systemic medical history and conditions 
1. Any type of systemic disease or its treatment, including any medical condition (controlled 
or uncontrolled) that could be expected to progress, recur, or change to such an extent that 
it may bias the assessment of the clinical status of the patient to a significant degree or put 
the patient at special risk. 
2. Stroke or myocardial infarction less than 3 months prior to screening. 
3. Presence of uncontrolled systolic blood pressure > 160 mmHg or diastolic blood pressure 
> 100 mmHg at the time of screening or baseline. 
4. Type 1 or Type 2 diabetes mellitus according to ADA (2014) and/or WHO (2006) 
classifications (see Appendix 2, Table A2-2) with glycosylated hemoglobin (HbA1c) > 


Novartis Pharma 
Confidential 
Page 19 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
10% (> 86 mmol/mol) at screening. Diabetic patients should be on diet, exercise and/or 
pharmacological treatment for diabetes, which must have been stable for at least 3 months.  
5. Known hypersensitivity to any of the study drugs or to drugs with similar chemical 
structures or to fluorescein or any other component of fluorescein formulation. 
Exclusion criteria for ocular medical history and conditions 
For either eye  
6. Any active periocular or ocular infection or inflammation at the time of screening or 
baseline  
7. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication or 
according to investigator’s judgment) at the time of screening or baseline. 
8. Neovascularization of the iris or neovascular glaucoma at the time of screening or 
baseline. 
For study eye 
9. Atrophy or fibrosis involving the center of the fovea at the time of screening or baseline. 
10. Cataract (if causing significant visual impairment), planned cataract surgery during the 
study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage, 
rhegmatogenous 
retinal 
detachment, 
proliferative 
retinopathy 
or 
choroidal 
neovascularization of any other cause than wAMD (e.g., ocular histoplasmosis, pathologic 
myopia) at the time of screening or baseline. 
11. Irreversible structural damage within 0.5 disc diameter of the center of the macula 
(e.g., vitreomacular traction, epiretinal membrane, scar, laser burn, macular hole) at the 
time of screening or baseline that in the investigator’s opinion could preclude visual 
function improvement with treatment. 
For fellow eye 
12. Retinal or choroidal neovascularization or macula edema requiring treatment of any cause 
at the time of screening or baseline or the anticipation of development of the above 
mentioned medical conditions requiring treatment within 3 months past screening or 
baseline. 
Exclusion criteria for prior or current systemic medication 
13. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives from screening, whichever is longer. 
14. Use of any systemic anti-VEGF drugs (e.g., bevacizumab [Avastin®], ziv-aflibercept 
[Zaltrap®]).  
15. Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3 months 
prior to screening. 


Novartis Pharma 
Confidential 
Page 20 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
16. Current or planned use of systemic medications known to be toxic to the lens, retina or 
optic nerve, including deferoxamine, chloroquine/hydroxychloroquine (Plaquenil®), 
tamoxifen, phenothiazines and ethambutol. 
Exclusion criteria for prior or current ocular treatment 
For study eye 
17. Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet 
capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months 
following baseline. 
18. Use of intravitreal or topical ocular corticosteroids administered for at least 30 consecutive 
days within 3 months prior to screening.  
For either eye 
19. History of treatment with any anti-angiogenic drugs (including any anti-VEGF agents, 
e.g., bevacizumab [Avastin®]). 
Exclusion criteria for patient 
20. Inability to comply with study or follow-up procedures.  
21. Inability to give full informed consent. 
22. Women 
o who are pregnant or breast feeding (pregnancy defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/ml)) 
o who are menstruating and capable of becoming pregnant* and not practicing a medically 
approved method of contraception (Pearl Index <1**) during and up to at least 3 months 
after the end of treatment. A negative pregnancy test (serum) for all women and for girls 
entering menarche is required with sufficient lead time before inclusion  
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 
months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post 
surgical bilateral oophorectomy with or without hysterectomy 
**examples of particularly reliable methods with Pearl Index (PI) <1, according to 
guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: 
 hormonal oral contraception (Combination of estrogen and gestagen (, PI=0.1-0.9) 
 hormonal vaginal ring (combination of estrogen and gestagen, PI=0.65 uncorr.; 0.4 
corr.) 
 hormonal transdermal patch (combination of estrogen and gestagen PI= 0.72 uncorr.; 
0.9 corr.) 
 Estrogen-free ovulation inhibitors (containing desogestrel (PI=0.14) 
 Implanted hormones containing etonogestrel (PI=0-0.08) 
 Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) 
 Intra-uterine progestine device (synthetic progestin containing IUDs, PI=0.16) 


Novartis Pharma 
Confidential 
Page 21 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Oral contraceptives without estrogen (e.g. "mini-pills"), nonsynthetic progesterone only 
IUDs, female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
23. Patients, who have already been randomized into this trial earlier must not be included a 
second time. 
24. Study personnel or first degree relatives of investigator(s) must not be included in the 
study 
 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons: 
 Withdrawal of informed consent 
 Pregnancy  
 Any prohibited treatment that leads to study withdrawal as listed in table 6-1. 
Patients who discontinue study drug should NOT be considered withdrawn from the study. 
See Section 6.6.9 for the required assessments of these patients after study drug 
discontinuation. 
Patients also should be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason. Protocol violations should not lead to patient 
withdrawal unless they indicate a significant risk to the patient’s safety. 
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 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by newly 
enrolled patients. 
 


Novartis Pharma 
Confidential 
Page 22 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
6 
Treatment 
6.1 
Patient numbering 
Each patient in the study is uniquely identified by a 9 digit number which is a combination of 
his/her 4-digit center number and 5-digit subject number. The center number is assigned by 
Novartis to the investigative site. Upon signing the informed consent form, the patient is 
assigned a patient number by the investigator. At each site the first patient is assigned patient 
number 1, and subsequent patients are assigned consecutive numbers (e.g., the second patient 
is assigned patient number 2, the third patient is assigned patient number 3). Once assigned to 
a patient, a patient number will not be reused for any other patient and number for that 
individual must not be changed, even if the patient is re-screened. If the patient fails to be 
randomized for any reason, the reason for not being randomized will be entered on the 
Screening Log. 
 
6.2 
Investigational drugs 
Commercial available ranibizumab and aflibercept specially marked for clinical study only 
(“Zur klinischen Prüfung bestimmt”) will be used and supplied in the study.  
Ranibizumab and aflibercept must be stored according to the label instructions and must be 
kept in a secure locked facility. 
Novartis will provide sufficient supplies of ranibizumab and aflibercept for treatment use to 
allow for completion of the study 
6.2.1 
Ranibizumab 
The investigational drug in study group 1 from week 1 to week 24 and for study group 2 from 
week 12 to week 24 is 0.5 mg ranibizumab (Lucentis®). 
Ranibizumab solution for injection in vials or prefilled syringes will be used. Ranibizumab is 
formulated as a sterile solution aseptically filled in a sterile glass vial or sterile prefilled 
syringe. Each vials or prefilled syringe contains ranibizumab in an aqueous solution (pH 5.5) 
with histidine, trehalose, and polysorbate 20. Each vial or prefilled syringe is for single use 
only. Each vials or prefilled syringe will be labeled with the appropriate information. 
Each patient will either be treated only with ranibizumab in vials or only treated with 
ranibizumab in prefilled syringes throughout the entire study. 
6.2.2 
Aflibercept 
Investigational treatment drug in study group 2 from week 1 to week 8 is 2 mg aflibercept 
(Eylea®).  
Aflibercept solution for injection will be supplied in commercially available packaging. 
Aflibercept is formulated as a sterile solution aseptically filled in a sterile glass vial. Each vial 


Novartis Pharma 
Confidential 
Page 23 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
contains aflibercept in an aqueous solution with monosodium phosphate, disodium phosphate, 
sodium chloride, sucrose and polysorbate 20. The vials are suitable for single use only. Each 
vial will be labeled with the appropriate information.  
 
6.3 
Treatment arms 
Patients will be assigned to one of the following two treatment groups (=arms) in a ratio of 
1:1: 
 Group 1: Six monthly intravitreal injections of 0.5 mg ranibizumab 
 Group 2: Three monthly intravitreal injections of 2 mg aflibercept followed by 
three monthly intravitreal injections of 0.5 mg ranibizumab 
 
6.4 
Treatment assignment 
At visit 2 (baseline) all patients who meet the inclusion and do not fulfill any of the exclusion 
criteria will be given the card with the lowest available randomization number. This number 
will be assigned to the patient by the physician, who will enter the patient randomization 
number on the CRF. The physician will then look up the corresponding treatment on the 
allocation card (containing randomization numbers and corresponding treatment arm) and 
administer the study treatment accordingly.  
The patient randomization numbers will be generated using the following procedure to ensure 
that treatment assignment is unbiased and concealed from patients and evaluating staff: A 
patient randomization list will be produced by or under the responsibility of Novartis using a 
validated system.  
 
6.5 
Treatment blinding 
Given that the primary endpoint variable will be assessed by a blinded central laboratory, it is 
considered to be adequate that the injecting physician will not be blinded to treatment. The 
injecting physician has no influence on treatment regimen or primary or secondary endpoint 
assessments. The study will therefore be performed as a single-blinded study. Only patients, 
, reading center staff, laboratory staff and data analysts 
will remain blind to the identity of the treatment from the time of randomization until 
database lock, using the following methods: Randomization data are kept strictly confidential 
until the time of unblinding, and will not be accessible by blinded staff involved in the study. 
The study center staff or the physician must be vigilant not to unblind the patient, 
 
 Novartis personnel, the reading center or central laboratory to the treatment. The 
physician is responsible for keeping the treatment allocation cards in a secure locked place 
where
 has access to.  
Unblinding will only occur at the conclusion of the study. 


Novartis Pharma 
Confidential 
Page 24 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
6.6 
Treating the patient 
6.6.1 
Dispensing the study drug 
Ranibizumab and aflibercept medication will be supplied as commercially available Lucentis® 
or Eylea® with an additional label stating that it is being used in a clinical study. 
6.6.2 
Instructions for use of study drug 
Intravitreal injections will be administered as described in the SmPC for Lucentis® and 
Eylea®. 
After eligibility confirmation at baseline (day 1), patients will receive treatment according to 
their assignment into one of the two treatment groups (=arms) (see Sections 6.6.2.1 and 
6.6.2.2).  
The prefilled syringe or the vial will be taken from the package and treatment will be 
performed. After that the prefilled syringe (with needle removed) or empty vial will be put 
back in the commercial package and should be marked with patient number by the physician 
to make drug accountability possible. It will be stored at a secured locked and different 
location than unused packages and commercial (non-study) packages to avoid mix-up. 
All dosages prescribed and dispensed to the patient must be recorded on the Drug 
Administration Record CRF. 
The storage conditions for study drug will be described on the medication label. 
6.6.2.1 
Treatment group 1 
Beginning at baseline, patients randomized to the study group 1 will receive monthly 
intravitreal injections of 0.5 mg ranibizumab (visit 2, 6, 8, 10, 12 and 14) 
The interval between two intravitral injections should not be shorter than 28 days. 
6.6.2.2 
Treatment group 2 
Patients randomized to the study group 2 will receive three initial monthly injections of 2 mg 
aflibercept (visit 2, 6 and 8). This is followed by three monthly intravitreal injections of 0.5 
mg ranibizumab (visit 10, 12 and 14). 
The interval between two intravitreal injections should not be shorter than 28 days. 
6.6.2.3 
Treatment of the fellow eye 
Patients, who develop an indication at the fellow eye that, in the investigator’s opinion, 
qualifies for and requires treatment, may be treated at the investigator’s discretion according 
to the standard of care. Administration of treatment to the fellow eye must be recorded on the 
Concomitant medication/Significant non-drug therapies page of the CRF (dose, timing and 
type of treatment).   
Anti-VEGF treatment of the fellow eye leads to study withdrawal.  


Novartis Pharma 
Confidential 
Page 25 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
6.6.3 
Study drug supply and resupply, storage, and tracking 
Study drugs 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 physician and designated 
assistants have access. Upon receipt, all study drugs should be stored according to the 
instructions specified on the drug labels.  
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the field monitor during site visits and at the completion of the trial.  
At the conclusion of the study and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.  
6.6.4 
Study drug compliance and accountability 
6.6.4.1 Study drug compliance 
Dosing frequency and compliance will be assessed by the investigator and/or study personnel 
at each patient visit and information provided by the patient will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit. 
6.6.4.2 Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in the Drug Accountability Log. Drug accountability will be noted by the 
field monitor during site visits and at the completion of the study. Investigators will be asked 
to keep all unused study drug and packaging until monitoring of drug accountability. 
6.6.5 
Disposal and destruction 
After drug accounting has been checked by monitor, at study close-out and, as appropriate 
during the course of the study, all used and unused study treatment, packaging, drug labels, 
and drug accounting forms will be returned to Novartis for destruction. 
6.6.6 
Permitted study drug dose adjustments and interruptions 
Dose adjustments, i.e., adjustments of the injection volume of ranibizumab or aflibercept dose 
solution, are not permitted.  
Ranibizumab and aflibercept treatment should be withheld and treatment should not be 
resumed earlier than the next scheduled treatment in the event of: 
 
 
 An IOP of ≥30 mm Hg, 
 An untreated retinal tear is diagnosed, 


Novartis Pharma 
Confidential 
Page 26 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 A subretinal hemorrhage involving the center of the fovea, or, if the size of the 
hemorrhage is ≥50%, of the total lesion area,  
 A performed or planned intraocular surgery within the previous or next 28 days. 
All interruptions must be recorded on the Drug Administration Record CRF. 
6.6.7 
Rescue medication 
Rescue medication is not forseen in this study. 
6.6.8 
Other concomitant treatment 
Use of treatments, as displayed in Table 6-1 is NOT allowed after screening. In addition, there 
are certain wash-out periods to be respected as outlined in the list of exclusion criteria. 
Table 6-1 
Prohibited treatment 
Medication 
Action to be taken 
Systemic or ocular (fellow eye) anti-VEGF drugs  
Study withdrawal 
Intra- or periocular corticosteroids (including sub-Tenon but 
excluding topical formulations) – study eye  
Study withdrawal 
Medications known to be toxic to the lens, retina or optic 
nerve 
including 
deferoxamine, 
chloroquine/ 
hydroxychloroquine (Plaquenil®), tamoxifen, phenothiazines, 
and ethambutol 
To be recorded in the CRF 
Other investigational drugs and investigational interventions 
of any type 
To be recorded in the CRF 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after enrollment 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 in the CRF.  
Protocol specific medications (e.g., dilating drops, fluorescein dyes) and pre- and post-
injection medications (e.g., topical anesthetics) used by a patient during the study are not 
considered concomitant medications. 
Patients who are prematurely withdrawn from the study should be scheduled for visit 16 as 
soon as possible, at which time all of the assessments listed for the final visit will be 
performed.  
6.6.9 
Study drug discontinuation 
Patients can discontinue study treatment because of the appearance of a new health condition 
suspected to require appropriate, unacceptable AEs, refusal to continue treatment, or at the 
investigator’s discretion based on his or her clinical judgment. 


Novartis Pharma 
Confidential 
Page 27 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. The following 
circumstances require study drug discontinuation: 
 Emergence of the following adverse events: 
– macular hole (stage 3 or 4) in the study eye 
– rhegmatogenous retinal detachment in the study eye 
– transient ischemic attack (TIA) or a stroke during the study  
 Any other protocol deviation that results in a significant risk to the patient’s safety. 
Patients who discontinue study treatment should not be considered withdrawn from the study 
and the investigator should encourage the patient to continue in the study and to return for the 
remaining visits as described in Table 7-1. 
In addition, all the criteria listed under 5.2 for premature patient withdrawal will automatically 
lead to study drug discontinuation. In addition to these requirements for study drug 
discontinuation, the investigator should discontinue study drug for a given patient if, on 
balance, he thinks that continuation would be detrimental to the patient’s well-being. 
6.6.10 
Emergency unblinding of treatment assignment 
Emergency code break cards are not applicable since the investigator is unblinded.  
6.6.11 
Study completion and post-study treatment 
The study will be considered completed for an individual patient when he/she completes study 
visit 16.  
Patients who already have entered the Screening Period should not enter the Treatment Period 
once the planned number of patients has been found eligible to commence treatment in the 
study.  
The study can be terminated for reasons stipulated in the study contract. Should this be 
necessary, the patients should be contacted and scheduled for their end of study assessments 
as described in Section 7. Novartis will be responsible for informing IRBs and/or IECs of the 
early termination of the study.  
The investigator also must provide follow-up medical care for all patients who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care.  
 


Novartis Pharma 
Confidential 
Page 28 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
7 
Visit schedule and assessments 
Table 7-1 lists all of the patient`s assessments and indicates with an “X” the visits when they 
are performed.  
A planned study visit schedule will be established at the time of baseline visit (day 1) for all 
patients. Study assessments for patients will be performed at screening visit, baseline (day 1), 
day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day 
169 at biweekly visits (defined as every 14 days calculated from baseline; ± 4 days to allow 
for flexibility in scheduling).  
Should a deviation from the study visit schedule occur, all efforts should be made to return to 
the planned visit schedule taking into consideration the restrictions on the minimum treatment 
interval between ranibizumab or aflibercept  treatments, which should be ≥ 28 days. 
Study site personnel will contact each patient via telephone 2 days (± 1 day) after each study 
treatment to elicit reports on AEs. If in consequence clinical assessment is required, patients 
will be scheduled to return to the site for an unscheduled visit and all findings will be 
recorded on the unscheduled visit assessment CRF. Patients will be further instructed to 
contact their investigator at any time should they have health-related concerns. 
Patients who are prematurely withdrawn from the study for any reason should be scheduled 
for visit 16 as soon as possible, at which time all of the assessments listed for the final visit 
will be performed.  
Patients who discontinue study drug before completing the study should be encouraged to 
return for the remaining visits as described in Table 7-1. If they refuse to return for these 
assessments or are unable to do so, every effort should be made to contact them or a 
knowledgeable informant by telephone to determine the primary reason. At a minimum, they 
will be contacted for safety evaluations during the 30 days following the last dose of study 
drug, including final contact at the 30-day point. Documentation of attempts to contact the 
patient should be recorded in the patient record. 
All data obtained from the assessments listed in Table 7-1 and described in detail in the 
subsections below must be supported in the patient’s source documentation.  


Novartis Pharma 
Confidential 
Page 29 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Table 7-1 
Assessment schedule for patients 
Period 
SCN 
BSL 
  
EOS 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Study month (relative to Day 1) 
  
1 
2 
3 
4 
5 
6 
7 
Days (relative to Day 1) 
 -14 to -1 
1 
2 
8 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
Visit window (days) 
  
  
± 1 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
Information & Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Diagnosis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior/concomitant medication 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photography 
X a 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X a 
Fluorescein Angiography 
X a 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X a 
Ophthalmoscopy (Fundus)  
X a 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X a 
Anterior Biomicroscopy (Slit lamp) 
X a 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X a 
Tonometry 
X a 
X b 
  
  
  
X b 
  
X b 
  
X b 
  
X b 
  
X b 
  
X a 
Adverse events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Pulse rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test c 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 


Novartis Pharma 
Confidential 
Page 30 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Urine sample 
  
  
X 
  
  
  
  
  
X 
  
  
  
X 
Treatment: Group 1 
Ranibizumab 
  
Xd 
  
  
  
Xd 
  
Xd 
  
Xd 
  
Xd 
  
Xd 
  
  
Treatment Group 2 
Aflibercept  
  
Xd 
  
  
  
Xd 
  
Xd 
  
  
  
  
  
  
  
  
Ranibizumab 
  
  
  
  
  
  
  
  
  
Xd 
  
Xd 
  
Xd 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
a= Assessment to be performed also on fellow eye 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
b= Tonometry has to be performed before and after drug administration. 
  
  
  
  
  
  
  
  
  
  
  
  
c=For women of child-bearing potential, serum pregnancy test at screening, urine pregnancy test at the end of study 
  
  
  
  
  
  
d= Including post-injection assessment after intravitreal injection according to investigator’s judgment, such as vision check, optic nerve head perfusion 
  
  
  
 


Novartis Pharma 
Confidential 
Page 31 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
7.1 
Information to be collected on screening failures 
Only demography data and the reason for failing (screening failure log) are collected for those 
patients who fail to enter the study phase. Blood samples of screening failures will be 
discarded. 
Potential adverse events and hospitalizations which may have occurred from time of signing 
informed consent/written assent until screening failure time should be documented in the 
patient medical records. Reporting of potential SAE during this time period should be 
followed as described in Section 8.2. 
 
7.2 
Demographics/other baseline characteristics 
The following information will be collected/documented at screening (visit 1) and/or baseline 
(visit 2): 
 Year of birth  
 Age 
 Sex 
 Race 
 Past medical history and current medical conditions 
 Prior/ concomitant medications  
 Vital signs 
 Study eye  
 CNV lesion type and location 
 
 
 Area of CNV lesion and CNV leakage on FA, presence of hemorrhage on CF 
 Infection status by using slit lamp examination  
 Intraocular pressure  
 
 
 Pregnancy testing  
 Blood sampling for assessment of systemic VEGF levels, 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 Smoking status 


Novartis Pharma 
Confidential 
Page 32 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
7.3 
Treatment exposure and compliance 
Treatment exposure will be assessed for the study eye. Information regarding study treatment 
administration or any protocol deviations of treatment administration in the study eye will be 
collected on the Drug Administration Record CRF.  
Any deviations from the protocol in use of prohibited medications (e.g. anti-VEGF) during 
the study will be collected on the Concomitant medications/Significant non-drug therapies 
page of the CRF. 
 
7.4 
Efficacy 
The assessment for the primary endpoint, systemic VEGF-A plasma protein concentration, is 
described in Section 7.9.  
Efficacy assessments will include both functional and anatomical evaluations. The methods of 
evaluation and the parameter to be assessed are listed below.  
 
 
These patient’s assessments are performed according to the schedule in Table 7-1. All 
efficacy assessments are to be done on the patient`s study eye and recorded in the CRF. 


Novartis Pharma 
Confidential 
Page 33 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
7.4.3 
Color Fundus Photography and Fluorescein Angiography 
Patients must be assessed using the same camera throughout the course of the study. 
Fluorescein angiography (FA) is to be done in conjunction with color fundus photography 
(CF) at screening/visit 1 and visit 16 for both eyes, and color fundus photography of the study 
eye only at visit 2 and 10. Investigators will use digital fluorescein angiograms to determine 
the presence or absence of CNV secondary to AMD. 
FA and CF image files will be exported, labeled, saved to DVD and sent to the central CRC 
following the instructions in the clinical site instruction manual. 
A copy of the photographs and angiograms will be retained with the source documents. 
All CRC staff performing the assessments of FA and CF images will be blinded to the identity 
of the treatment. 
Novartis requires certification for FA evaluation. An operations manual and training materials 
for the certification will be provided by the central reading center. Certification will occur 
prior to any evaluation of study patients. 


Novartis Pharma 
Confidential 
Page 34 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 
7.5 
Safety 
7.5.1 
Adverse events 
For details on adverse event collection and reporting, refer to Section 8. 
7.5.2 
Physical examination 
No physical examination will be performed. 
7.5.3 
Vital signs 
The results will be recorded in the Vital Signs CRF. Clinically notable vital signs are defined 
in Appendix 2, Table A2-1.  
At visits when treatment is administered, vital signs will be measured prior to the intravitreal 
injection. 
7.5.3.1 
Height and weight 
Height in centimeters (cm) will be measured at visit 2. 
Body weight (in indoor clothing, but without shoes) will be measured at visits 2, 10 and 16. 
7.5.3.2 
Pulse rate 
At each visit, the pulse rate (beats per minute-bpm) will be measured in the sitting position for 
30 seconds just prior to the blood pressure measurements. 
7.5.3.3 
Blood pressure 
At each study visit, after the patient has been sitting for at least five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood pressures will be 
measured three times using an automatic blood pressure monitor and appropriate size cuff.  
The repeat sitting measurements will be made with approximately 3 minute resting intervals 
in between and the mean of these three blood pressure measurements will be used as the 
average sitting blood pressure for that visit (mmHg) and will be recorded in the patient’s 
source documents and CRF. 
At the first study visit, sitting blood pressure should be measured in both arms and the arm in 
which the highest sitting diastolic blood pressure is found will be the arm used for all 
subsequent readings throughout the study and should be documented in the source documents.  
7.5.4 
Laboratory evaluations 
No specific laboratory evaluations for safety assessment will be performed. Laboratory 
evaluations for serum pregnancy testing, pharmacodynamics 
 are 
described in Sections 7.5.5, 7.9 and 7.11, respectively. 


Novartis Pharma 
Confidential 
Page 35 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
7.5.5 
Pregnancy test and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
screening (visit 1) and a urine pregnancy test at the end of study (visit 16). Results will be 
recorded in the respective CRF. A central laboratory will be used for analysis of the serum.  
7.5.6 
Eye-specific safety monitoring 
The standard ophthalmic examinations include slit lamp examination, anterior chamber 
examination, direct and indirect ophthalmoscopy of the macular and peripheral retina, and 
tonometry. They will be performed as indicated in the assessment schedule (Table 7-1). Slit 
lamp and fundus examinations will be performed prior to treatment with ranibizumab or 
aflibercept. 
The test results will be recorded in the source documents and clinically significant 
abnormalities will be recorded on the medical/ocular history page (if occurring before BSL) 
and if occurring after the first injection with investigational drug, on adverse event page of the 
CRF. 
7.5.6.1 
Anterior segment biomicroscopy (slit lamp examination) 
Prior to administration of treatment, the anterior segment’s structures of the study eye will be 
carefully examined. If needed, an additional examination will be performed after application 
of any study medication. Fellow eye will be examined at screening (visit 1) and visit 16 and 
during the study on discretion of the investigator. 
7.5.6.2 
Ophthalmoscopy 
At the screening (visit 1) and visit 16 the posterior segment of both eyes will be examined by 
the investigator on dilated pupil using adequate ophthalmoscopy apparatus in order to confirm 
the clinical findings compatible with CNV secondary to wAMD as inclusion criteria’s 
assessments. Also a careful examination of the peripheral retina must be conducted to ensure 
that the intravitreal injection can safely be performed (i.e. iatrogenic retinal detachment, 
should not be receive intravitreal injections).  
At the indicated visits from baseline (visit 2) on, assessment of the posterior of the study eye 
will be performed and recorded by the investigator and an additional examination if needed 
will be performed after the application of the study medication. If the patient experiences 
blurred vision and light flashes at any time, the investigator should perform the indirect 
ophthalmoscopy examination in order to detect any AEs and apply the appropriate treatment. 
In case of uncertainty regarding the clinical findings at the macular area with 
ophthalmoscopy, a complementary examination using a suitable lens through slit lamp 
apparatus can be done for the study eye by the investigator.  
7.5.6.3 
Intraocular pressure (IOP) 
Both eyes IOP will be measured at screening (visit 1) and visit 16. Pre-dose IOP in the study 
eye will be assessed by the investigator or trained technician at every scheduled visit as from 


Novartis Pharma 
Confidential 
Page 36 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
visit 2 (day 1) and post-dose IOP will be assessed 15 to 60 minutes after injection in the study 
eye. The values will be recorded in mmHg and will be entered into the CRF.  
In case intraocular pressure is ≥25 mmHg in the study eye, and if not transient, for any reason 
and at any time during the study period, treatment and closer monitoring of IOP should be 
performed by the investigator in order to achieve similar values to the baseline measurement. 
In this case, intravitreal procedure is not recommended unless normalization of the IOP has 
been achieved. The investigator should treat appropriately the increased IOP in order to allow 
the patient to continue in the study. In addition, at the discretion of the investigator and/or 
according to the local requirements/practices, monitoring of optic nerve head perfusion may 
be appropriate within 30 minutes after injection. Results of these procedures will be recorded 
in the source documents. Only if the findings constitute an AE they have to be recorded in the 
AE CRF. 
 
7.6 
Tolerability/acceptability 
Tolerability of the treatment will be assessed through AE reporting in this study.  
 
7.7 
Resource utilization  
Data for Healthcare Resource Allocation will not be collected for this study 
 
7.8 
Health-related Quality of Life 
Halth-related Quality of Life will not be collected for this study 
 
7.9 
Pharmacokinetics/pharmacodynamics 
7.9.1 
Pharmacodynamics 
A central laboratory will be used for analysis of systemic VEGF (-A,
) plasma 
levels of all specimens collected. If an intravitreal injection is administered at the same visit, 
blood sampling must be conducted prior to administration of the drug. Blood samples will be 
taken as shown in assessment schedule in Table 7-1. Blood sampling at visit 3 should be 
performed 24 h ± 2 h after blood sampling at visit 2. Details on the collections, labelling, 
storage and shipment of samples are provided to investigators in the laboratory manual. 
All central laboratory staff performing the assessments of systemic VEGF plasma protein 
levels will be blinded to the identity of the treatment. 
7.10 
Pharmacogenetics/pharmacogenomics 
Not applicable. 


Novartis Pharma 
Confidential 
Page 37 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 
 


Novartis Pharma 
Confidential 
Page 38 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
8 
Safety monitoring 
8.1 
Adverse events 
8.1.1 
Adverse event definition and reporting 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after first intake of study drug even if the event is not considered 
to be related to study drug. Study drug includes the investigational drug under evaluation and 
the comparator drug or placebo that is given during any period of the study. 
Medical conditions/diseases present before first administration of study drug are only 
considered adverse events if they worsen after study start. Abnormal laboratory values or test 
results constitute adverse events only if they induce clinical signs or symptoms, require dose 
reduction or temporary or permanent study drug discontinuation or require therapy. 
All adverse events with a date of onset up to 30 days following the last dose of study drug 
must be reported. 
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. All adverse events must be recorded on the Adverse Events CRF with the 
following information: 
1. the severity grade (mild, moderate, severe)  
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its relationship to the ocular injection (suspected/not suspected) 
4. its duration (start and end dates or if continuing at final exam) 
5. whether it constitutes a serious adverse event (SAE) 
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 drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. 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, seriousness, the suspected relationship to the study 
drug, the interventions required to treat it, and the outcome. 
8.1.2 
Laboratory test abnormalities 
Laboratory abnormalities that constitute an Adverse Event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require dose reduction or temporary 
or permanent study drug discontinuation or require concomitant therapy), should be recorded 


Novartis Pharma 
Confidential 
Page 39 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
on the Adverse Event CRF page. Whenever possible, a diagnosis, rather than a symptom 
should be provided. Laboratory abnormalities that meet the criteria for an Adverse Event 
should be followed until they have returned to normal or an adequate explanation of the 
abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events.  
A grade 3 or 4 event or laboratory abnormality (severe) as per CTCAE (if applicable) does not 
automatically indicate an SAE unless it meets the definition of serious as defined below 
and/or as per investigator´s discretion. If a lab event satisfies the regulatory definition of 
“Serious”, such an event must be reported to Novartis within 24 hours of learning of its 
occurrence. Any laboratory SAEs experienced 30 days after completion of the study period 
should only be reported to Novartis if the investigator suspects a causal relationship to the 
study treatment. 
 
8.2 
Serious adverse events 
8.2.1 
 Serious adverse event definition, treatment and follow-up 
An SAE is defined as an event which: 
 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 the start of study drug 
 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 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; SAEs in contrast to AEs need to be reported from informed 
consent on, see Section 8.2.2.  


Novartis Pharma 
Confidential 
Page 40 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure or Summary of product characteristics, respectively, 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. 
8.2.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. For patients who discontinue 
study medication, SAEs still need to be reported until the end of study, regardless of their 
suspected relationship to study medication.  
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 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 German 
Novartis Clinical Safety & Epidemiology Department. The telephone and telefax number of 
the contact persons in the German department of Clinical Safety and Epidemiology, are listed 
in the investigator folder provided to each site. The original copy of the SAE Report Form and 
the fax confirmation sheet must be kept with the case report form documentation at the study 
site. 
All serious AEs occurring during the follow-up will be entered in the Adverse Events CRF 
pages. In addition, an SAE Report Form should be completed. Follow-up information is sent 
to the same person to whom the original SAE Report Form was sent, using a new SAE Report 
Form stating that this is a follow-up to the previously reported SAE and giving the date of the 
original report. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a Clinical Safety & 
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. 


Novartis Pharma 
Confidential 
Page 41 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
8.3 
Pregnancy reporting 
To ensure patient safety, each pregnancy in a patient on study drug 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.  
Instances of pregnancies and positive pregnancy tests should be collected for all patients who 
have conceived after receiving study medication. Pregnancies that are noted prior to 
administration of study medication but after signing informed consent may require reporting if 
they are considered to be associated to the conduct of the study by the investigator. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the German Novartis Clinical Safety & Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
8.4 
Reporting of adverse events and pregnancies after the last dose 
of study drug taken 
All AEs, SAEs, and pregnancies which occurred within 30 days after intake of last dose of 
study drug should be reported. After this 30-day period, only SAEs, and pregnancies should 
be reported until the last visit. 
 
8.5 
Data Monitoring Board 
Not applicable. 


Novartis Pharma 
Confidential 
Page 42 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
9 
Data review and database management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit, 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 drug is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, 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. 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 the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
 
9.2 
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 Data Management by field 
monitors, one copy being retained at the investigational site. Once the CRFs are received by 
Data Management, their receipt is recorded and they are reviewed prior to data entry.  
 
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research Organization 
staff following their own internal standard operating procedures that have been reviewed and 
approved by Novartis. 


Novartis Pharma 
Confidential 
Page 43 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Errors are corrected by 
Data Management personnel as preliminary corrections. 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. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Fluorescein angiograms, color fundus photographs and 
 will be processed 
centrally by the reading center and the results will be sent electronically to Novartis (or a 
designated CRO). 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and the treatment codes will be unblinded and made available 
for data analysis. Any changes to the database after that time can only be made by joint 
written agreement between the Trial Statistician and Statistical Reporting and the Clinical 
Trial Leader. 
 
10 
Data analysis 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator(s) should be submitted to Novartis before 
publication or presentation 
It is planned that the data from all centers that participate in this protocol will be used, so that 
an adequate number of patients will be available for analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, pharmacokinetic and 
pharmacodynamic measurements, 
. 
 
10.1 
Populations for analysis 
The Randomized Set (RS) will consist of all patients who were randomized to one of the 
treatment arms. 


Novartis Pharma 
Confidential 
Page 44 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
The Full Analysis Set (FAS) will consist of all patients as randomized who receive at least 
one application of study treatment and have at least one post-baseline assessment of the 
primary efficacy variable (plasma VEGF-A concentration). Following the intent-to-treat 
principle, patients will be analyzed according to the treatment they were assigned to at 
randomization. No data will be excluded from the FAS analyses because of protocol 
deviations. 
The Safety Set will consist of all patients that received at least one application of study 
treatment and had at least one post-baseline safety assessment. Patients will be analyzed 
according to treatment received. Of note, the statement that a patient had no adverse events 
also constitutes a safety assessment. 
The Per-Protocol Set (PPS) will consist of all patients who did not show major deviations 
from the protocol procedures that might have an impact on the study outcome. Criteria that 
are assumed to have such an impact will be defined in the data validation document (VAP) 
and in the Blind Review Protocol before unblinding. 
The primary analysis will be performed for both, the FAS and the PPS. The PPS is regarded 
as primary. FAS will be interpreted in terms of sensitivity analysis. 
 
10.2 
Patient demographics/other baseline characteristics 
Descriptive statistics will be provided for patient demographics and all baseline characteristics 
(including the baseline values of the efficacy endpoints).  
Relevant medical history (ocular and non-ocular) and current medical conditions will be 
tabulated by system organ class and preferred term of the MedDRA dictionary. Separate 
tables will be provided for ocular (in study eye and fellow eye) and non-ocular histories and 
conditions. Other relevant baseline information will be listed and summarized as appropriate 
with descriptive statistics. 
Analyses on patient demographics will be based on the RS. 
 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
10.3.1 
Investigational Treatment 
Descriptive statistics will be provided for exposure to study treatment using the Safety Set. 
The number of ranibizumab and aflibercept injections will be presented by treatment arm in 
frequency tables by visit and cumulatively. 
10.3.2 
Concomitant therapies 
The number and percentage of patients taking concomitant therapies will be summarized by 
preferred term according to the WHO Drug Reference List dictionary using the Safety Set. 


Novartis Pharma 
Confidential 
Page 45 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Summaries will be presented over two time periods: therapies received prior to the start of 
study treatment and therapies received after the start of study treatment. 
 
10.4 
Analysis of the primary objective(s) 
10.4.1 
Variable 
The primary variable is the area under the curve (AUC) of VEGF-A protein concentration in 
plasma measured between day 2 and study week 12. The AUC will be standardized 
(=divided) by the individual follow-up time and will be calculated by the trapezoidal rule.  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The null hypothesis states no difference in systemic VEGF-A levels between ranibizumab and 
aflibercept monthly therapy, measured by an AUC. The level of significance is 5% two-sided. 
The primary analysis will be performed by an analysis of covariance (ANCOVA) model with 
the factors center and treatment taking into account the baseline systemic VEGF-A level as a 
covariate. Raw- as well as adjusted (LS-) means with corresponding 95% confidence intervals 
and p-values will be calculated as point estimates for the treatment contrasts.  
Multiplicity issues are not applicable because there is only one primary comparison. As there 
is very little knowledge about the distribution of systemic VEGF-A levels and especially on 
the variability, a blinded pooled interim analysis of the Variance of VEGF-A levels is planned 
to possibly adapt the planned sample size only, as described below.  
10.4.3 
Handling of missing values/censoring/discontinuations 
The primary endpoint measure is calculated as an AUC and any patient not providing any post 
baseline value into the analysis is defined not to be included in the FAS. Consequently, there 
is no need to impute for missing values. In case there are only one or two out of the eight 
values for a patient, the area change can still be calculated preventing any dropouts other than 
those with no post baseline measurements. 
10.4.4 
Supportive analyses 
The primary analysis will be repeated for the FAS to evaluate robustness of the results of the 
primary analysis. In case of relevant deviations from the normal distribution, non parametric 
analyses may be taken into account. Furthermore, careful examination of the distribution of 
the VEGF-levels will be prepared for the blind review meeting. If outliers or other properties 
of the distribution make it seem more appropriate, a log-transformation of the data or 
multiplicatory models will be taken into account, even for primary analysis if this is deemed 
reasonable. Also an analysis using relative changes instead of absolute differences in VEGF 
levels may be considered in case this is deemed reasonable during blind review. 
Furthermore, descriptive subgroup analyses will be prepared to explore gender differences for 
primary results. 


Novartis Pharma 
Confidential 
Page 46 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 
10.5 
Analysis of secondary objectives 
To compare systemic VEGF-A protein levels in patients switching from monthly 2 mg 
aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with 
monthly 0.5 mg ranibizumab from baseline. The analysis will be performed following the 
same methods as for the primary analysis taking into account the levels measured between 
week 12 and 24. 
To explore whether systemic VEGF-A levels of patients switching from aflibercept to 
ranibizumab will adjust to levels comparable to baseline or to levels comparable as in patients 
treated from baseline with ranibizumab from study week 12, over time up to week 24 
10.5.2 
Safety 
Safety analyses will be based on adverse events, vital signs, laboratory evaluations, 
ophthalmic examinations and IOP. 
All safety analyses will be performed using the Safety Set.  
Adverse Events  
AEs will be deemed treatment emergent if the onset date is on or after the date of first study 
treatment. AEs recorded prior to the start of study treatment will be listed separately. Only 
treatment-emergent AEs will be summarized.  


Novartis Pharma 
Confidential 
Page 47 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
AEs will be summarized by presenting for each treatment arm the number and percentage of 
patients having any AE, having an eye-related AEs, having an AE in each primary system 
organ class and having each individual AEs based on the preferred term. Patients who 
experienced multiple AEs for a preferred term will be counted once, similarly for patients 
with multiple AEs per system organ class.  
All other information collected (e.g., severity or relationship to study treatment) will be 
tabulated and listed as appropriate. Summary tables will also be presented for the subset of 
AEs suspected to be treatment related.  
Vital signs and IOP measurements will be presented descriptively (absolute values and change 
from baseline). Results from ophthalmic examinations will be listed. 
Deaths, SAEs, and AEs leading to discontinuation of study treatment will be listed separately 
and, if appropriate, summarized by primary system organ class and preferred term.  
For a given treatment period in the crossover design of treatment arm 2, the only AEs that will 
be counted for that treatment will be treatment-emergent events. These events are those that 
started after the start of that treatment period, or were present prior to the start of the treatment 
period but increased in severity, changed from being not suspected to being suspected to be 
due to study drug, or developed into an SAE after the start of the treatment period 
10.5.3 
Tolerability 
Tolerability will not be assessed separately and will be included in the AE reporting. 
10.5.4 
Pharmacokinetics/ pharmacodynamics 
10.5.4.1 Pharmacodynamics 
Please also refer to Section 10.4.1 for the analysis of the primary objective variable and to 
Section 10.5 for the analysis of the secondary objective variable.  
 
 
 
  
 
 
 
 
  


Novartis Pharma 
Confidential 
Page 48 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
 
10.6 
Interim analysis 
There is only very little knowledge about the distribution of systemic VEGF-A levels and 
especially on the variability. Thus, as an over- or underestimation of the variance and 
consequently of the standardized effect size might jeopardize the adequacy of the planned 
sample size, a blinded pooled interim evaluation of the variance of VEGF-A levels is planned 
when 20 patients (10 in each treatment arm) completed study week 12 to possibly adapt the 
planned sample size only. This analysis is intended to adjust the sample size if necessary 
while limiting the interventions (e.g. blood sampling) to as little patients as necessary. No 
further treatment unblinding and especially no interim efficacy analysis will be performed. 
This interim analysis will not use any unblinded data, therefore no adjustment of the type-1-
error levels is required. 
 
10.7 
Sample size calculation 
In the past, measuring systemic VEGF protein levels was performed differently in the 
literature available. While some authors used blood plasma (Avery 2013; Carneiro 2012; 
Zehetner 2013), others used blood serum (Chakravarthy 2012). In addition, individual 
systemic VEGF levels seem to be very variable, depending e.g. on the state of health, 
hormone levels or menstrual cycle.  
To date, only one study investigated the pharmacodynamic effect of aflibercept on systemic 
VEGF protein levels (Avery 2013). Given that aflibercept features an Fc part, a similar 
transport mechanism for aflibercept over the blood-retina-border as for bevacizumab can be 
hypothesized. 
Given that individual systemic VEGF-A levels seem to be variable, a change of ±20% from 
baseline to study week 12 is considered clinically irrelevant. It is expected that the change of 
systemic VEGF-A protein levels from baseline to study week 12 following aflibercept 
treatment is >20%. A difference in change of ≥25% of systemic VEGF-A protein reduction 
between the two treatment arms from baseline to study week 12 is considered reasonable to 
show different effects of the two drugs on systemic VEGF-A plasma levels.  
While the calculation of the sample size was performed using percentages due to the huge 
variability of baseline VEGF-A levels in the present data, it is assumed that the equivalent 
effect size will result from the area under the curve as endpoint variable.  
A large standardized effect size of 1,25 was assumed (which would lead to an estimated 
common standard deviation of the change in VEGF-A levels of 20%). 15 patients per group 
are required to achieve 90% power on a 2-sided 5% significance level. To compensate for 
some dropouts and other protocol violations such as treatment of the fellow eye with anti-
VEGF treatments, 20 patients per treatment arm (40 total) should be recruited into this trial.  
As only baseline values and standard deviation for systemic VEGF-A levels are variable in all 
published studies to date, a blinded pooled analysis of the variance for the primary endpoint 
parameter will be performed when 20 patients (10 in each treatment arm) completed study 


Novartis Pharma 
Confidential 
Page 49 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
week 12. This analysis is intended to adjust the sample size if necessary while limiting the 
interventions (blood sampling) to as little patients as necessary.    
10.8 
Power for analysis of critical secondary variables 
Not applicable. 
 
11 
Discussion and rationale for study design features  
Study drug regimen and treatment design 
Ranibizumab and aflibercept are both approved medications for the treatment of wAMD. 
They will be administered at the doses and according to the regimens recommended in the EU 
SmPC from baseline to study week 12. Thereafter, all patients will receive monthly 
ranibizumab injections.  
Given that the sample size of the two study arms will be very small, application of a pro re 
nata regimen from study week 12 to study week 24 would result in very variable treatment 
patterns of the patients. Since this would limit the conclusions of this part of the study, 
monthly injection intervals were chosen. 
At study week 12, patients in study group 2 will be switched from aflibercept to ranibizumab 
therapy in order to explore whether systemic VEGF levels adjust to levels comparable to 
baseline or to levels comparable as in patients treated with ranibizumab from baseline.  
Randomization and Blinding 
This is a single-blinded study where the investigator is not blinded to treatment but treatment 
assignment is randomized and consecutive enrollment will be used to help reduce bias. Given 
that the primary endpoint variable will be assessed by a blinded central laboratory, it is 
considered to be adequate that the injecting physician will not be blinded to treatment. The 
injecting physician has no influence on treatment regimen or primary or secondary endpoint 
assessments. A central laboratory and central reading center that is masked to treatment 
assignment will be used in order to ensure unbiased evaluation of the primary, secondary and 
exploratory objectives. The patient 
 are also blinded to treatment 
assignment. 
Assessments 
All study procedures related to the assessment of safety and efficacy are well established in 
the field of ophthalmologic clinical research or are non-invasive. 
Interim analysis 
There is only very little knowledge about the distribution of systemic VEGF-A levels and 
especially on the variability. Thus, as an over- or underestimation of the variance and 
consequently of the standardized effect size might jeopardize the adequacy of the planned 
sample size, a blinded pooled interim evaluation of the variance of VEGF-A levels is planned 
to possibly adapt the planned sample size only. 


Novartis Pharma 
Confidential 
Page 50 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
12 
References 
American Diabetes Association (2014) Diagnosis and Classification of Diabetes Mellitus. 
Diabetes Care, vol. 37, (Suppl. 1), p.81-90. 
Avery R (2013) Comparison of Systemic Pharmacokinetics Post-Anti-VEGF Intravitreal 
Injections of Ranibizumab, Bevacizumab and Aflibercept. Data presented at ASRS Annual 
Meeting, Toronto CA, 25th August 2013. 
Carneiro AM, Costa R, Falcão MS et al. (2012) Vascular endothelial growth factor plasma 
levels before and after treatment of neovascular age-related macular degeneration with 
bevacizumab or ranibizumab. Acta Ophthalmol, vol. 90 (1), p. e25-30. 
Chakravarthy U, Harding SP, Rogers CA et al. (2012) Ranibizumab versus bevacizumab to 
treat neovascular age-related macular degeneration: one-year findings from the IVAN 
randomized trial. Ophthalmology, vol. 119 (7), p. 1399-411. 
Chakravarthy U, Harding SP, Rogers CA et al. (2013) Alternative treatments to inhibit VEGF 
in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised 
controlled trial. The Lancet, vol. 382 (9900), p. 1258-67. 
Chen HX & Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF 
pathway. Nat Rev Clin Oncol, vol 6 (8), p.465-77. 
Chong V (2012) Biological, preclinical and clinical characteristics of inhibitors of vascular 
endothelial growth factors. Ophthalmologica, vol. 227 (Suppl 1), p. 2-10. 
Coleman HR, Chan C-C, Ferris F et al. (2008). Age-related macular degeneration. The 
Lancet, vol. 372, p.1835-45.  
Cruess AF & Giacomantonio N (2014) Cardiac Issues of Noncardiac Drugs: The Rising Story 
of Avastin in Age-Related Macular Degeneration. Ophthalmologica, vol. 231 (2), p. 75-9. 
Dhoot DS & Kaiser PK (2012) Ranibizumab for age-related macular degeneration. Expert 
Opin Biol Ther, vol. 12 (3), p.371-81.  
European Medicines Agency CHMP assessment report on Eylea (aflibercept), Procedure No. 
EMEA/H/C/002392/ 
(2012) 
[Available 
at 
http://www.ema.europa.eu/docs/en_GB/ 
document_library/EPAR_-_Public_assessment_report/human/002392/WC500135744.pdf 
(accessed on 4th March 2014)] 
European Medicines Agency (2013) Avastin Summary of product characteristics [Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ 
human/000582/WC500029271.pdf (accessed on 11th March 2014)] 


Novartis Pharma 
Confidential 
Page 51 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
European Medicines Agency (2013) Eylea Summary of product characteristics [Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ 
human/002392/WC500135815.pdf (accessed on 11th March 2014)] 
European Medicines Agency (2014) Lucentis Summary of product characteristics [Available 
at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ 
human/000715/WC500043546.pdf (accessed on 11th March 2014)] 
Ferrara N, Damico L, Shams N et al. (2006) Development of ranibizumab, an anti-vascular 
endothelial growth factor antigen binding fragment, as therapy for neovascular age-related 
macular degeneration. Retina, vol. 26 (8), p. 859-70 
Ferreira A, Sagkriotis A, Milnes F et al. (2013) Treatment patterns of ranibizumab and 
aflibercept for the management of wet age-related macular degeneration in routine clinical 
practice in the US. Data presented at the ISPOR Annual European Congress Dublin, IR. 
Harding SP, Rogers CA, Downes SM et al. (2013) Alternative treatments to inhibit VEGF in 
age-related choroidal neovascularization (IVAN): two-year results. Data presented at ARVO 
Annual 
Meeting, 
Seattle, 
WA, 
7th 
May 
2013. 
[Available 
at 
http://www.prolibraries.com/player/?embed=4f24e70fb86805a2009c5b47a4a5d025# 
(accessed on 4th March 2014)] 
Kaiser PK, Cruess AF, Bogaert P et al. (2010) Balancing risk in ophthalmic prescribing: 
assessing the safety of anti-VEGF therapies and the risks associated with unlicensed 
medicines. Graefes Arch Clin Exp Ophthalmol, vol. 250, p.1563-71.  
Kim H, Robinson SB, Csaky KG (2009) FcRn receptor-mediated pharmacokinetics of 
therapeutic IgG in the eye. Mol Vis, vol. 15, p. 2803-12.  
Kovach JL, Schwartz SG, Flynn H et al, (2012) Anti-VEGF treatment strategies for wet 
AMD. J Ophthalmol, 786870.doi:10.1155/2012/786870.  
Lee S, Chen TT, Barber CL, et al. (2007) Autocrine VEGF signaling is required for vascular 
homeostasis. Cell, vol 130, p. 691–703. 
Mordenti J, Cuthbertson RA, Ferrara N et al (1999) Comparisons of the intraocular tissue 
distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in 
rhesus monkeys following intravitreal administration. Toxicol Pathol. vol. 27(5), p. 536-44. 
Ozkiris A (2010) Anti-VEGF agents for age-related macular degeneration. Expert Opin Ther 
Patents, vol 20 (1), p.103-18.  
Raghavan M & Bjorkman PJ (1996) Fc receptors and their interactions with 
immunoglobulins. Annu Rev Cell Dev Biol; vol. 12, p. 181–220. 


Novartis Pharma 
Confidential 
Page 52 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Reff ME, Hariharan K, Braslawsk G (2002) Future of monoclonal antibodies in the treatment 
of hematologic malignancies. Cancer Control. vol 9(2), p. 152-66. 
WHO/IDF consultation report (2006) Definition and diagnosis of diabetes mellitus and 
intermediate 
hyperglycaemia 
[Available 
at 
http://whqlibdoc.who.int/publications/ 
2006/9241594934_eng.pdf (accessed on 24th March 2014] 
Yeung YA, Wu X, Reyes AE 2nd et al. (2010) A therapeutic anti-VEGF antibody with 
increased potency independent of pharmacokinetic half-life. Cancer Res, vol. 70 (8), p. 3269-
77. 
Zehetner C, Kirchmair R, Huber S et al. (2013) Plasma levels of vascular endothelial growth 
factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in 
patients with age-related macular degeneration, and in patients with diabetic macular oedema. 
Br J Ophthalmol, vol. 97 (4), p. 454-9. 
 


Novartis Pharma 
Confidential 
Page 53 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Appendix 1: Ethical considerations and administrative procedures 
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.  
Responsibilities of the investigator and IRB/IEC/ 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board / Independent Ethics Committee (IRB/IEC) before study start. 
Approval letters concerning protocol and informed consent will be filed by Novartis. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to conduct 
the study in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
Informed consent procedures  
Eligible patients may only be included in the study after providing written, IRB/IEC-approved informed 
consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for 
this study. 
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 no authorized deviations are permitted. If the investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC it cannot be implemented. All significant protocol deviations will be recorded and reported in 
the CSR. 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC. Only amendments that are 
required for patient safety may be implemented prior to IRB/IEC approval. Notwithstanding the need 
for approval of formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a deviation 
from the protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed within 10 working days. 


Novartis Pharma 
Confidential 
Page 54 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical trial 
agreement. 
Publication of study design 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 study will be either submitted for publication and/or posted in a publicly 
accessible database of clinical study results. 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. As part of participating in a Novartis-sponsored study, each 
site will permit authorized representatives of the sponsor(s) and regulatory agencies to examine (and 
when required by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. The study case report form (CRF) is the primary data collection instrument for 
the study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported in the CRFs and all other required reports. Data reported on the CRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies should 
be explained. All data requested on the CRF must be recorded. Any missing data must be explained. 
Any change or correction to a paper CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry. For electronic CRFs an audit trail will be maintained by the 
system. The investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential Documents for 
the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and/or 
guidelines. The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than fifteen 
(15) years from the completion of the Clinical Trial unless Sponsor provides written permission to 
dispose of them or, requires their retention for an additional period of time because of applicable laws, 
regulations and/or guidelines. 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names in 
any documents submitted to Novartis. Signed informed consent forms and patient enrollment log must 
be kept strictly confidential to enable patient identification at the site. 
Audits and inspections  
Source data/documents must be available to inspections by Novartis or designee or Health Authorities 


Novartis Pharma 
Confidential 
Page 55 
Clinical Study Protocol including Amendment 2 
 
Study No. CRFB002ADE27 
 
 
Version 02 (27.04.2015) 
 
 
 
 
 
 
Appendix 2: Clinically notable laboratory values and vital signs 
 
Critical values for vital signs are defined in Table A2-1. Baseline critical values are 
defined by the absolute values only. 
Table A2-1 
Critical values  
Variable  
Type of abnormality 
Critical values 
Systolic blood pressure 
(mmHg) 
High 
Either >180 with an increase from 
baseline > 30 or > 200 absolute 
Low 
Either < 90 with a decrease from  
baseline > 30 or < 75 absolute 
Diastolic blood pressure 
(mmHg) 
High 
Either >105 with an increase from 
baseline > 20 or > 115 absolute 
Low 
Either < 50 with a decrease from  
baseline > 20 or < 40 absolute 
Pulse rate (bpm) 
High 
Either > 120 with an increase from 
baseline > 25 or > 130 absolute 
Low 
Either < 50 with a decrease from  
baseline > 30 or < 40 absolute 
 
Table A2-2 
Criteria for the diagnosis of diabetes  
WHO 2006 
ADA 2014 
Fasting plasma glucose ≥ 126mg/dL (7.0mmol/L) 
                                                            Or 
Two-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test 
n/a 
Or 
HbA1c ≥ 6.5% 
Or 
In a patient with classic symptoms of hyperglycemia 
or hyperglycemic crisis, 
a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L). 
 

SAP_001.pdf: 
Clinical Development
RFB002/Ranibizumab/Lucentis®
CRFB002ADE27 / NCT02257632
A randomized, single-blinded, multicenter, phase IV study to 
compare systemic VEGF protein dynamics following monthly 
intravitreal injections of 0.5 mg ranibizumab versus 2 mg 
aflibercept until study week 12 in patients with neovascular 
(wet) age-related macular degeneration (TIDE AMD)
Statistical Analysis Plan (SAP)
Author:
;
;
Document type:
SAP Documentation: Amendment
Document status:
Final version 1.0
Release date:
10-NOV-2017
Number of pages:
29
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
CRFB002ADE27
Table of contents
Table of contents .................................................................................................................2
List of abbreviations............................................................................................................4
1
Introduction .........................................................................................................................6
Study design.............................................................................................................6
Study objectives and endpoints ...............................................................................7
Primary objective ....................................................................................7
Secondary objective(s)............................................................................7
8
2
Statistical methods...............................................................................................................9
Data analysis general information ...........................................................................9
General definitions................................................................................10
End of study visit ..................................................................................10
Unscheduled visits ................................................................................11
Analysis sets ..........................................................................................................11
Subgroup of interest ..............................................................................13
Patient disposition, demographics and other baseline characteristics ...................13
Patient disposition.................................................................................13
Background and demographic characteristics.......................................13
Medical history......................................................................................15
Treatments (study treatment, concomitant therapies, compliance) .......................15
Study treatment / compliance................................................................15
Prior and concomitant therapies............................................................16
Analysis of the primary objective..........................................................................16
Primary endpoint...................................................................................16
Statistical hypothesis, model, and method of analysis..........................16
Handling of missing values/censoring/discontinuations.......................17
Supportive analyses...............................................................................17
Analysis of the key secondary objective ...............................................................17
Analysis of secondary objective(s)........................................................................18
Secondary endpoints .............................................................................18
Statistical hypothesis, model, and method of analysis..........................18
Handling of missing values/censoring/discontinuations.......................18
Safety analyses.......................................................................................................18
Adverse events (AEs)............................................................................19
Deaths....................................................................................................19


Novartis
For business use only
Page 3
SAP
CRFB002ADE27
Laboratory data .....................................................................................20
Other safety data ...................................................................................20
Pharmacokinetic endpoints....................................................................................21
PD and PK/PD analyses.........................................................................................21
Patient-reported outcomes .....................................................................................21
21
21
Interim analysis......................................................................................................22
3
Sample size calculation .....................................................................................................22
4
Change to protocol specified analyses ..............................................................................22
5
Appendix ...........................................................................................................................23
Imputation rules.....................................................................................................23
AE date imputation ...............................................................................23
Concomitant medication date imputation .............................................24
Other imputations..................................................................................26
Efficacy variables and populations for analysis ....................................................26
SAS code for analysis ...........................................................................27
Clinically notable laboratory values and vital signs ..............................................27
Rule of exclusion criteria of analysis sets..............................................................28
Reference..................................................................................................................................28


Novartis
For business use only
Page 4
SAP
CRFB002ADE27
List of abbreviations
AE
Adverse event
ANCOVA
Analyses of covariance
AMD
Age-related macular degeneration
AUC
Area under the curve
BLQ
Below the limit of quantification 
BMI
Body mass index
CI
Confident interval
CNV
Choroidal neovascularization
CSF
Case Report Form
CSR
Clinical study report
eCRF
electronic Case Report/Record Form
EOS
End of study
EOT
End of treatment
FA
Fluorescein angiography
FAS
Full analysis set
FCP
Foveal center point
FP
Color fundus photography
gCV
Geometric coefficient
gMean
Geometric mean
HbA1c
Glycosylated hemoglobin
IA
Interim analysis
IOP
Intraocular pressure
LS
Least squares
MedDRA
Medical Dictionary for Drug Regulatory Affairs
PD
Protocol deviation
PK
Pharmacokinetics
PRO
Patient-reported outcome
PPS
Per-protocol set
PT
Preferred term
RPE
Retinal pigment epithelium
RS
Randomized set 
SAEs
Serious adverse events 
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error


Novartis
For business use only
Page 5
SAP
CRFB002ADE27
SI
Standard international
SOC
System organ class
SRF
Subretinal Hyporeflective Space
TEAE
Treatment emergent AE
VEGF
Vascular endothelial growth factor
wAMD
Neovascular (wet) age-related macular degeneration
WHO
World health organization


Novartis
For business use only
Page 6
SAP
CRFB002ADE27
1
Introduction
This statistical analysis plan (SAP) describes the statistical analysis according to Section 10 of 
the study protocol (version no. 2 including Amendment 2) along with any additional analyses, 
specifications or deviations from this protocol planned before unmasking of the data.
 
 
 Determination of sample size is 
specified in Section 3.
Study design
This is a randomized, single-blinded, multicenter, phase IV study to compare systemic 
vascular endothelial growth factor (VEGF)-A protein levels following monthly intravitreal 
injections of 0.5 mg ranibizumab versus monthly intravitreal injections of 2 mg aflibercept 
until study week 12 in patients with active, newly diagnosed, untreated neovascular (wet) age-
related macular degeneration (AMD).
From week 12 (visit 10) on all patients will receive monthly intravitreal injections of 0.5 mg 
ranibizumab until study week 20 (visit 14) in order to compare systemic VEGF-A protein 
levels from study week 12 to week 24 (visit 16) in patients switching from aflibercept to 
ranibizumab injections with patients treated with ranibizumab only.
Patients with wAMD will be randomized to one of the following treatment groups: 
Treatment group 1 (n=20): Monthly intravitreal injections of 0.5 mg ranibizumab for six 
months
Treatment group 2 (n=20): Monthly intravitreal injections of 2 mg aflibercept for the 
initial three months followed by monthly intravitreal injections of 0.5 mg ranibizumab for 
the next three months.
A blinded central laboratory will evaluate systemic VEGF-A plasma levels.
The study requires 16 study visits during 24 weeks and the primary endpoint will assess data 
from baseline to study week 12 (visit 10).


Novartis
For business use only
Page 7
SAP
CRFB002ADE27
Figure 1-1
Study outline
Study objectives and endpoints
Primary objective
The primary object of this study is as follows:
To compare systemic VEGF-A protein levels (based on the SIMOA assay method) 
following monthly intravitreal injections of 0.5 mg ranibizumab for three months versus 
monthly 2 mg aflibercept injections for three months as measured by the area under the 
curve (AUC) from baseline to week 12 (visit 10).
Secondary objective(s)
The secondary objectives of this study are as follows:
To compare systemic VEGF-A protein levels (based on the SIMOA assay method) in 
patients switching from monthly 2 mg aflibercept injections for first three months to 
monthly 0.5 mg ranibizumab injections for the next three months compared to patients 
treated with monthly 0.5 mg ranibizumab for six months at specific time points as 
measured by the AUC from week 12 (visit 10) to week 24 (visit 16).
To explore whether systemic VEGF-A levels (based on the SIMOA assay method) of 
patients switching from monthly 2 mg aflibercept injections for first three months to 
monthly 0.5 mg ranibizumab injections for the next three months will adjust to levels 
comparable to baseline or to levels comparable as in patients treated with monthly 0.5 mg 
ranibizumab for six months at specific time points from week 12 (visit 10), over time up 
to week 24 (visit 16).


Novartis
For business use only
Page 8
SAP
CRFB002ADE27


Novartis
For business use only
Page 9
SAP
CRFB002ADE27
2
Statistical methods
Data analysis general information
The analysis will be performed by 
. SAS® 
statistical software (Version 9.4 or a more recent version) will be used for analysis.
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations 
and 
measurements, 
safety 
observations 
and 
measurements,
and 
pharmacodynamic measurements.
Descriptive statistics (the number of non-missing observations, mean, median, standard 
deviation [SD], minimum and maximum values) will be presented for continuous variables. 
The following number of decimal places will be used: mean and median values to 1 more 
decimal place than the raw data; minimum and maximum to the same number of decimal 
places as the raw data and SD to 2 more decimal places than the raw data. If required (e.g. for 
AUC), the geometric mean (gMean) will be derived by calculating the mean of the natural log 
transformed individual values. This value will then be back transformed to give the geometric 
mean.
The study eye is the eye selected by the investigator at baseline (according to the protocol) to 
receive the study treatment. The fellow eye is the non-study eye.
Assessments documented in the database as occurring in “both eyes” will be summarized for 
each eye separately. 
Medications, Significant Non-drug Therapies and Adverse Events (AEs) will be defined as 
ocular or non-ocular according to the investigator’s response to ‘ophthalmic relevance’ on the 
relevant electronic Case Report/Record Form (eCRF) page.
The safety observation period for the exposure to treatment will be presented separately for:
Comparative phase: From baseline (Day 1) to the last visit the patient attended up to and 
including the week 12 visit (note: although the date of the week 12 visit is used fo r
derivation of period when injections are summarized the week 12 injection is not part of 
comparative phase)  
Switch phase: From week 12 to the last visit the patient attended up to and including the 
week 24 visit (week 24).
Overall treatment period: From baseline to the last visit the patient attended up to and 
including the week 24 visit. 
Safety observation period (days) is defined as (date of study completion – date of first 
administration of treatment) + 1.
Change from baseline will only be summarized for patients with both baseline and post-
baseline values at the relevant visit and will be calculated as:
Change from baseline = post-baseline value – baseline value.
All data will be listed by patient, unless stated otherwise.


Novartis
For business use only
Page 10
SAP
CRFB002ADE27
General definitions
This study will consist of the following epochs (refer to Figure 1-1):
a screening period,
a treatment period (comparative and switch phases).
The treatment comparative phase is from Day 1 (visit 2) up to week 12 (visit 10). Treatment 
switch phase is from week 12 (visit 10) up to week 24 (visit 16).  
Study treatment refers to:
Ranibizumab (Lucentis®)

The investigational treatment in treatment group 1 from week one (visit 2) to week 24 
(visit 16) and for treatment group 2 from week 12 (visit 10) to week 24 (visit 16) is 
0.5 mg ranibizumab (Lucentis®). 
Aflibercept (Eylea®)

Investigational treatment in treatment group 2 from week one (visit 2) to week 8 (visit 
8) is 2 mg aflibercept (Eylea®). 
Baseline is the date of first administration of study treatment in the study eye. Baseline value 
will be considered as the value of the last non-missing assessment collected prior to start of 
treatment (i.e. data from screening or baseline). If a patient is randomized but not treated then 
the baseline value for a variable is the last available non-missing value collected prior to 
randomization.
Some baseline assessments may be recorded on the day of the baseline visit (visit 2). However 
the time of each of these assessments may not be recorded in the eCRF. In this case, only the 
assessments which, according to the protocol, should have been conducted pre-dose will be 
assumed to have been done before the first study treatment in the study eye when deriving 
baseline values recorded on the day of the baseline visit (visit 2). 
All data collected after Day 1 are defined as post-baseline.
End of study visit
Analyses presented by visit will use the visits and visit numbers as recorded in the database. 
No visit windows will be defined except for the End of Study (EOS) visit (see below). EOS
visits will be denoted by visit number 777 in the database.
The study day for the EOS visit will be allocated to the nearest planned visit. 
Study day will be calculated relative to Day 1: 
Study day = (Date of visit) – (Date of baseline visit) + 1.
Table 2-1
Allocation of end of study visit
Visit number
Analysis Visit
Scheduled visit day
Visit window 
(study days)
1
Screening
<1
-14 - (-1)
2
Baseline/Day 1
1
1
3
Day 2
2
2 - 4


Novartis
For business use only
Page 11
SAP
CRFB002ADE27
Visit number
Analysis Visit
Scheduled visit day
Visit window 
(study days)
4
Week 1
8
5 - 11
5
Week 2
15
12 - 21
6
Week 4
29
22 - 35
7
Week 6 
43
36 - 49
8
Week 8
57
50 - 63
9
Week 10
71
64 - 77
10
Week 12
85
78 - 91
11
Week 14
99
92 - 105
12
Week 16
113
106 - 119
13
Week 18
127
120 - 133
14
Week 20
141
134 - 147
15
Week 22
155
148 - 161
16
Week 24
169
≥162
If data for the nearest planned visit already exist then the EOS visit will be assigned to the 
next visit.
For example, consider a patient with planned visits at study days -7, 1, 2, 8, 15 and 29. If this 
patient’s EOS visit were at day 57 then the allocated scheduled visit would be 8. If however 
the EOS visit were at day 40 then the allocated scheduled visit would be 7.
Unscheduled visits
All data collected at unscheduled visits will be listed.
Exposure and AEs data collected at unscheduled visits will be summarized. No other data 
from unscheduled visits will be summarized.
Analysis sets
The Randomized Set (RS) will consist of all patients who were randomized to one of the 
treatment arms.
The Full Analysis Set (FAS) will consist of all patients as randomized who receive at least 
one application of study treatment and have at least one post-baseline assessment of the 
primary efficacy variable (plasma VEGF-A concentration). Following the intent-to-treat 
principle, patients will be analyzed according to the treatment they were assigned to at 
randomization. No data will be excluded from the FAS analyses because of protocol 
deviations.
The Safety Set will consist of all patients that received at least one application of study 
treatment and had at least one post-baseline safety assessment. Patients will be analyzed 
according to treatment received. Of note, the statement that a patient had no adverse events 
also constitutes a safety assessment.
The Per-Protocol Set (PPS) will consist of all patients in FAS who did not show major 
deviations from the protocol procedures that might have an impact on the study outcome. 


Novartis
For business use only
Page 12
SAP
CRFB002ADE27
Criteria that are assumed to have such an impact will be defined in the data validation 
document (VAP) and in the Blind Review Protocol before unblinding.
The primary analysis will be performed for both, the FAS and the PPS. The PPS is regarded 
as primary. FAS will be interpreted in terms of supportive analysis.
Rule of exclusion criteria of analysis sets see Appendix 5.4.
Table 2-2
Analysis data sets for specific outputs
All screened 
patients
RS
FAS
PPS
Safety 
Set
Screening failures
x
Demographics and baseline 
characteristics
x
x
Analysis sets
x
Patient disposition
x
x
Protocol deviations
x
Medical history
x
Concomitant medication
x
Primary endpoint
x
x
Secondary endpoints
x
x
Safety analyses
x
Exposure
x
Subgroup analyses
x
Sensitivity analyses
x
The number of patients included in each analysis set will be presented.
A listing will be produced to show the patient inclusion/exclusion into each of the analysis 
sets with the corresponding reason(s) for exclusion. 
The number of patients with clinical study report (CSR) reportable protocol deviations (PDs)
as defined in the data review plan will be summarized by category and PD. Patients with 
multiple occurrence of a PD will be presented once for that PD and patients with multiple 
occurrences of PDs within a category will be only counted once per category.
The PD categories are as follows:
Patient did not satisfy inclusion criteria
Patient met exclusion criteria
Patient received the wrong treatment or incorrect dose
Patient met compliance violation (unblinding)
Patient participated in treatment relevant visits out of schedule
Patient had missing values in the primary variable
Patient developed withdrawal criteria during the study, but not withdrawn
Patient took an excluded concomitant medication


Novartis
For business use only
Page 13
SAP
CRFB002ADE27
Others.
Patients removed from the RS will not appear in the summary of PDs. These patients will be 
documented in the output summarizing the patients excluded from analysis sets. 
Criteria defining PDs is outlined in the Appendix 5.4.
Subgroup of interest
Descriptive subgroup analyses will be prepared to explore gender differences for the primary 
endpoint.
Patients with missing baseline values used to define the subgroups will be presented in a 
category “unknown” in the respective subgroup analyses.
Patient disposition, demographics and other baseline 
characteristics
Patient disposition will be presented for RS and all the demographics and baseline 
characteristics will be presented for the FAS and PPS by treatment group and overall.
Patient disposition
The number and percentage of patients who are screen failures and reasons for screen failure 
will be presented for all patients screened. 
The number and percentage of patients who completed and discontinued the study (including 
primary reason for study discontinuation) will be summarized for the RS by treatment and 
overall.
All patient disposition data will be listed by treatment, center and patient number for the RS.
Background and demographic characteristics
Demographics and baseline data collected and documented at screening (visit 1) and/or 
baseline (visit 2) will be summarized for the FAS and PPS by treatment group and overall. 
The time from a pre-screening event (e.g. diagnosis of a condition or taking a medication) in 
days will be calculated in relation to date of informed consent.
Descriptive statistics will be provided for the below demographics and baseline characteristics:
Demographic variables and vital signs
Categorical variables:
Sex (Male, Female)
Predominant race (Caucasian, Black, Asian, Other)
Age group (<65, ≥65 years)
Smoking status (Never smoked, Current smoker, Ex-smoker)
Pregnancy testing for women of child-bearing potential (Negative, Positive, Not 
applicable)
Continuous variables:


Novartis
For business use only
Page 14
SAP
CRFB002ADE27
Age (years)
Vital signs: Height (cm), Weight (kg), Pulse (bpm), Systolic sitting blood pressure 
(mmHg), Diastolic sitting blood pressure (mmHg)
Body mass index (BMI) [kg/m²]
Estimated number of cigarette pack years 
Baseline ocular characteristics for study eye
Categorical variables:
Assessed by the site:

Study eye (left, right)

AMD baseline characteristics:
o
Presence of active CNV lesion due to neovascular AMD (Yes, No) 
o
Type of CNV lesion (Predominantly classic, Minimally classic, Occult, Not 
evaluable) 
o
Location of CNV lesion (Subfoveal, Juxtafoveal, Extrafoveal, Not evaluable)
Assessed by central reading center:

OCT variable:
o
Presence of Macular Edema (Yes, No, Questionable, Cannot grade) (study eye)

If Yes or Questionable: presence of Cystoid spaces (Yes, No, Questionable, 
Cannot grade)
o
Presence of Subretinal Hyporeflective Space (SRF) (Yes, No, Questionable, 
Cannot grade)
o
Presence of Epiretinal Membrane (Yes, No, Questionable, Cannot grade) 
o
Presence of Vitreomacular Traction (Yes, No, Questionable, Cannot grade)

Color fundus photography (FP) variable:
o
Presence of Intra-/subretinal or sub-Retinal pigment epithelium (RPE) Hemorrhage 
(Yes, No, Questionable, Cannot grade)

If Yes or Questionable: is it subfoveal (Yes, No, Questionable, Cannot 
grade)

Fluorescein Angiography (FA) variable:
o
Presence of CNV (Yes, No, Questionable, Cannot grade) 

If Yes or Questionable: presence of active CNV leakage (Yes, No, 
Questionable, Cannot grade) 
o
Type of CNV lesion (Predominantly classic, Minimally classic, Occult, Cannot 
grade)
o
Location of CNV lesion (Subfoveal, Juxtafoveal, Extrafoveal, Cannot grade)

General reading center:
o
Presence of other pathology (Yes, No, Questionable, Cannot grade)

If Yes or Questionable: other pathologies
o
Patients eligibility (Yes, No, Questionable, Cannot grade)

If No or Questionable: the reasons


Novartis
For business use only
Page 15
SAP
CRFB002ADE27
Continuous variables:
Assessed by site:

 

Intraocular pressure (IOP) (mmHg) 

AMD baseline characteristics:
o
Time since diagnosis of wAMD (weeks)
All demographic and baseline data will be listed by treatment, center and patient number for 
the FAS.
Medical history
The number and percentage of patients from the RS with relevant medical history and current 
medical conditions will be tabulated separately by system organ class (SOC) and preferred 
term (PT) from the current Medical Dictionary for Regulatory Activities (MedDRA). The 
SOCs will be presented in alphabetical order. PTs will be ordered for each treatment in 
decreasing proportion in the ranibizumab treatment group of interest (treatment group 1).
Separate tables will be provided for ocular and non-ocular histories and conditions. Ocular 
histories and conditions will also be presented separately for study and fellow eye.
Furthermore, medical history data will be listed by treatment, center, and patient number for 
the RS.
Treatments (study treatment, concomitant therapies, compliance)
Unless otherwise stated, all analyses will be based on patients in the Safety Set.
Study treatment / compliance
All treatment exposure will be presented for the study eye. It is not planned for the fellow eye 
to receive study treatment. 
Exposure is defined as the number of ranibizumab and/or aflibercept injections received for 
the safety observation period of interest. 
Descriptive statistics will be provided for exposure to study treatment for each safety 
observation epoch (see Section 2.1) using the Safety Set. The number of ranibizumab and 
aflibercept injections will be presented by treatment arm in frequency tables by visit and 
cumulatively.


Novartis
For business use only
Page 16
SAP
CRFB002ADE27
Prior and concomitant therapies
The number and percentage of patients taking concomitant therapies will be summarized by 
PT according to the World Health Organization (WHO) Drug Reference List dictionary. 
Summaries of the following will be presented:
Prior medications will be defined as drugs taken and stopped prior to baseline
Any medication given at least once between baseline and the last day of study visit will be 
a concomitant medication, including those which were started pre-baseline and continued 
into the treatment period.
For both, prior and concomitant therapies, summary tables will be presented for ocular 
therapies (separated for study eye and fellow eye) and non-ocular therapies. 
For handling of missing or incomplete start and end dates, see Section 5.1.2 of this document.
By-patient listings for prior and concomitant therapies will be provided.
Analysis of the primary objective
Only the study eye will be evaluated for efficacy. 
Primary endpoint
The primary variable is the AUC of systemic VEGF-A protein concentration in plasma (based 
on the SIMOA assay method) following monthly injections of ranibizumab or aflibercept 
monotherapy measured between Day 1 and study week 12. 
AUC will be calculated using the trapezoidal rule, where all available measurements between 
Day 1 and week 12 will be used.
	
 =  	

 × (	 + ) × (	 −)


Where dk represents scheduled day of visit k and Vk represents systemic VEGF-A levels at 
visit k. The AUC will be standardized by dividing the calculated value of the individual 
follow-up time (the number of days from first to last measurement). 
Range calculated as:
 ! −"#$ !
Where dlast and dfirst represents scheduled day of last and first systemic VEGF-A 
measurements in the visit range 2 to 10.
The analysis of the primary variable will be performed on the PPS. A further supportive 
analysis will be performed in the FAS (see Section 2.5.4). 
Statistical hypothesis, model, and method of analysis
The null and alternative hypothesis for the primary analysis is as follows:
H0: AUCRanibizumab –  AUCAflibercept = 0
H1: AUCRanibizumab –  AUCAflibercept ≠ 0


Novartis
For business use only
Page 17
SAP
CRFB002ADE27
The primary analysis will be performed by an analysis of covariance (ANCOVA) model 
including study treatment and center as factors and baseline systemic VEGF-A level as a 
covariate. The analysis will be performed at the two-sided 5% significance level. Least 
squares (LS) (“raw” and “adjusted”) means with corresponding two-sided asymptotic 95% 
confidence intervals (CIs) and p-values will be calculated as point estimates for the treatment 
contrasts. 
The assumptions of the above ANCOVA model (i.e. errors were independently normally 
distributed with constant variance) will be evaluated. Homogeneity of variance between/ 
among treatment groups will be evaluated visually. If the assumptions for ANCOVA are not 
met, a non-parametric ANCOVA analysis will be performed.
Descriptive statistics including the geometric mean and geometric coefficient of determination 
(gCV) for AUC based on systemic VEGF-A levels from Day 1 up to week 12 (visit 10) will 
also be presented.
Furthermore, summary statistics will be presented for systemic VEGF-A levels by visit. 
Absolute values, change from baseline, and percent change from baseline values for systemic 
VEGF-A levels will be displayed. 
Individual VEGF-A level profiles will be listed and also presented using line plots. Line plots 
will also be produced for the mean change from baseline values. 
Handling of missing values/censoring/discontinuations
For the primary endpoint, there will be no imputation of missing data as the AUC of systemic 
VEGF-A levels will be standardized by dividing by the calculated value of the individual 
follow-up time (the number of days from first to last measurement). For the primary analysis, 
missing baseline VEGF-A level covariate values will be imputed by the mean value of non-
missing baseline VEGF-A level from all the patients with values.
Patients with no visit 2 to 10 VEGF-A level data will be omitted from the primary endpoint 
analysis as per the PPS definitions given above (see Section 2.2). 
Supportive analyses
To assess for robustness of the results, the same ANCOVA model as specified for the primary 
analysis will be repeated for the FAS (on observed data).
In addition, the same ANCOVA model will be repeated without VEGF-A level covariate  
imputation for the PPS.  
Furthermore, gender subgroup analysis will be done for the primary analysis (based on PPS).
Analysis of the key secondary objective
There is no key secondary objective in this study.


Novartis
For business use only
Page 18
SAP
CRFB002ADE27
Analysis of secondary objective(s)
Secondary endpoints
The secondary endpoints are:
The AUC of systemic VEGF-A protein levels following monthly injections of ranibizumab 
monotherapy in both treatment groups measured between week 12 (visit 10) to week 24 (visit 
16).
The values of systemic VEGF-A protein levels following monthly injections of ranibizumab 
monotherapy in both treatment groups at each visit between week 12 (visit 10) and week 24 
(visit 16).
The analysis set for these analyses will be the PPS and FAS.
Statistical hypothesis, model, and method of analysis
There will be no hypothesis testing for the secondary endpoints and all analysis is to be 
interpreted in a purely descriptive manner.
The descriptive analysis will be performed following the same methods as for the primary 
analysis taking into account the levels measured between week 12 (visit 10) and 24 (visit 24) 
(see Section 2.5.2). 
In addition, summary statistics will be produced for the systemic VEGF-A protein baseline 
values, absolute values and the (percentage) change from baseline values from week 12 up to 
week 24 (visit 16) by visit. 
The course over time for the absolute values and for changes from baseline will be presented 
using line plots for the treatment groups for variable, showing the mean and standard error 
(SE) per visit.
Individual VEGF-A level profiles will be listed and as well presented using line plots. 
Handling of missing values/censoring/discontinuations
Handling of missing values in the secondary analysis will follow the similar approach as in 
the primary (see Section 2.5.3). There will be no imputation of missing data for the AUC of 
systemic VEGF-A protein levels. For the secondary analysis, missing baseline VEGF-A level 
covariate values will be imputed by the mean value of non-missing baseline VEGF-A level 
from all the patients with values. Patients with no visit 10 to 24 VEGF-A level data will be 
omitted from the analysis.
Safety analyses
Safety parameters will include AEs, vital signs, laboratory evaluations, ophthalmic 
examinations and IOP.
All safety analyses will be summarized by treatment using the Safety Set. No missing data 
will be imputed for safety analyses.


Novartis
For business use only
Page 19
SAP
CRFB002ADE27
Adverse events (AEs)
AEs will be deemed treatment emergent if the onset date is on or after the date of first 
treatment with investigational drug in the study eye or events present prior to start of study 
treatment but increased in severity on or after the first administration of study treatment in the 
study eye.
Only treatment emergent AEs (TEAEs) will be summarized. If any event has an incomplete 
onset date, this will be handled as described in the Appendix 5.1.1.
AEs will be coded by primary SOC and PT according to the latest version of M edDRA 
available at time of analysis. Patients who experienced multiple AEs for a PT will be counted 
once, similarly for patients with multiple AEs per SOC, unless specified otherwise.
The number and percentage of patients with ocular (study eye, fellow eye) and non-ocular 
AEs will be summarized separately by treatment group for the following categories:
All AEs
Serious adverse events (SAEs)
AEs suspected to be related to the study treatment
AEs suspected to be related to the ocular injection
AEs leading to study discontinuation
AEs by maximum severity (mild, moderate, severe)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs
which are not serious adverse events with an incidence greater than 5% and on treatment 
emergent SAEs and SAEs suspected to be related to study treatment will be provided by SOC
and PT on the Safety Set.
Furthermore, all AEs (AEs during the screening period, TEAEs, AEs during the 
post-treatment period) will be listed by treatment, center and patient number for the RS. This 
will also include details of the AE (e.g., verbatim given by the investigator as well as the 
primary SOC and PT), onset date, end date, severity, relationship to study treatment, 
relationship to ocular injection, whether it constitutes a SAE. 
The following AE listings will be provided:
All AEs
Deaths
SAEs
AEs leading to study treatment discontinuation
AEs suspected to be related to investigational study treatment and/ or ocular injection.
Deaths
Deaths (recorded on study completion CRF) will be listed as part of study disposition.


Novartis
For business use only
Page 20
SAP
CRFB002ADE27
Laboratory data
Serum pregnancy testing, pharmacodynamics  will be presented using standard international 
(SI) units. Laboratory data - observed values or changes from baseline values at each visit -
will be summarized using descriptive statistics. 
A shift table will be produced to summarize the shift from baseline to any laboratory values 
that are abnormally low or high. The clinical critical values are defined in Appendix 5.3. 
Baseline critical values are defined by the absolute values only. All data, including data from 
unscheduled visits, will be considered when identifying abnormal values.
Patient listings will be provided for all laboratory data. Values outside the clinical normal 
ranges will be flagged.
Other safety data
Vital signs
Vital signs (sitting systolic and diastolic blood pressure, pulse rate, height and weight) will be 
summarized by descriptive statistics, by visit, presenting absolute and change from baseline 
values. Change from baseline will only be summarized for patients with both baseline and 
post-baseline values.
Clinically notable values for certain vital sign measurements are defined in Appendix 5.3. 
Using these critical values, a shift table will be produced to summarize the shift from baseline 
to any vital signs values that are abnormally low or high. All data, including data from 
unscheduled visits, will be considered when identifying abnormal values.
Patient listings will be provided for all vital signs data and values outside the clinical normal 
ranges will be flagged.
Intraocular Pressure
IOP measurements (pre-injection and post-injection) will be summarized descriptively, by 
visit for absolute values and change from baseline (each visit for the study eye; final visit for 
fellow eye). 
Change from baseline will only be summarized for patients with both baseline and 
post-baseline values. 
In addition, the number and percentage of patients with IOP greater than or equal to ( ≥) 25
mmHg in the study eye will be presented by visit (pre-injection and post-injection).
All IOP data will be listed for all patients and IOP values ≥25 mmHg will be flagged.
Other safety assessments
Child bearing potential and serum and urine pregnancy test results (if applicable) will be listed 
for female patients.
Results from ophthalmic examination and post-injection safety assessments (not including 
IOP) results will be listed.


Novartis
For business use only
Page 21
SAP
CRFB002ADE27
Pharmacokinetic endpoints
There are no pharmacokinetic endpoints in this study.
PD and PK/PD analyses
Refer to Section 2.5 and Section 2.7 for PD analyses (AUC of systemic VEGF-A levels). 
There are no PK/PD analyses planned in this study.
Patient-reported outcomes
There are no patient-reported outcomes (PRO) analyses planned in this study.


Novartis
For business use only
Page 22
SAP
CRFB002ADE27
Interim analysis
Interim analysis (IA) was performed in order to verify the effect size assumed in the sample 
size calculation. Statistical analysis for IA is outlined in the IA SAP.
3
Sample size calculation
In the past, measuring systemic VEGF protein levels was performed differently in the 
literature available. While some authors used blood plasma (Avery 2013; Carneiro 2012; 
Zehetner 2013), others used blood serum (Chakravarthy 2012). In addition, individual 
systemic VEGF levels seem to be very variable, depending e.g. on the state of health, 
hormone levels or menstrual cycle. 
To date, only one study investigated the pharmacodynamic effect of aflibercept on systemic 
VEGF protein levels (Avery 2013). Given that aflibercept features an Fc part, a similar 
transport mechanism for aflibercept over the blood-retina-border as for bevacizumab can be 
hypothesized. 
Given that individual systemic VEGF-A levels seem to be variable, a change of ±20% from 
baseline to study week 12 is considered clinically irrelevant. It is expected that the change of 
systemic VEGF-A protein levels from baseline to study week 12 following aflibercept 
treatment is >20%. A difference in change of ≥25% of systemic VEGF-A protein reduction 
between the two treatment arms from baseline to study week 12 is considered reasonable to 
show different effects of the two drugs on systemic VEGF-A plasma levels. 
While the calculation of the sample size was performed using percentages due to the huge 
variability of baseline VEGF-A levels in the present data, it is assumed that the equivalent 
effect size will result from the AUC as endpoint variable. 
A large standardized effect size of 1,25 was assumed (which would lead to an estimated 
common standard deviation of the change in VEGF-A levels of 20%). 15 patients per group 
are required to achieve 90% power on a 2-sided 5% significance level. To compensate for 
some dropouts and other protocol violations such as treatment of the fellow eye with anti -
VEGF treatments, 20 patients per treatment arm (40 total) should be recruited into this trial. 
As only baseline values and standard deviation for systemic VEGF-A levels are variable in all 
published studies to date, a blinded pooled analysis of the variance for the primary endpoint 
parameter will be performed when 20 patients (10 in each treatment arm) completed study 
week 12. This analysis is intended to adjust the sample size if necessary while limiting the 
interventions (blood sampling) to as little patients as necessary.
4
Change to protocol specified analyses
Protocol section 3.1 determined the primary variable AUC of VEGF-A protein concentration 
in plasma to be measured between baseline and study week 12 whereas protocol section 
10.4.1 claimed the measure between Day 2 to study week 12. The assumption was made that 
section 10.4.1 mixed day 2 with visit 2 so decision was made to use AUC values from 
baseline to study week 12. 


Novartis
For business use only
Page 23
SAP
CRFB002ADE27
 
. 
Analyses on patient demographics will be based on the FAS and PPS rather than RS as 
defined in the protocol.
No other changes from the protocol specified analysis have been made.
5
Appendix
Imputation rules
AE date imputation
AE start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.c )
Uncertain
( 4.c )
After Treatment 
Start
YYYY > TRTY
( 3.a )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
Before imputing AE start date, find the AE start reference date.
If the (imputed) AE end date is complete and the (imputed) AE end date < investigational 
study treatment start date then AE start reference date = min (informed consent date, 
earliest visit date).
Else AE start reference date = investigational study treatment start date
Impute AE start date -
If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.
If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore:


Novartis
For business use only
Page 24
SAP
CRFB002ADE27
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JULYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid -month 
point (15MONYYYY).
If the AE start date year value is greater than the investigational study treatment start date 
year value, the AE started after treatment. Therefore:
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JANYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
If the AE start date year value is equal to the investigational study treatment start date year 
value:
a. And the AE month is missing the imputed AE start date is set to the AE reference start 
date + 1 day.
b. Else if the AE month is less than the investigational study treatment start month, the 
imputed AE start date is set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the investigational study treatment start date month or 
greater than the treatment start date month, the imputed AE start date is set to the later 
of (month start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date.
AE end date imputation
For the purpose of date imputation, the study treatment follow-up period date is defined as the 
last available visit date, i.e. including unscheduled visits after the EOS visit.
If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (study treatment follow-up period date, 31DECYYYY, date of death).
If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(study treatment follow-up period date, last day of the month, date of death).
If AE year is missing or AE is ongoing, the end date will not be imputed.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
Concomitant medication date imputation
CM start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY


Novartis
For business use only
Page 25
SAP
CRFB002ADE27
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.a )
Uncertain
( 4.c )
After Treatment 
Start
YYYY > TRTY
( 3.a )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
( 3.b )
After Treatment 
Start
If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date.
If the CM start date year value is less than the investigational study treatment start date 
year value, the CM started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid –year point 
(01JULYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
If the CM start date year value is greater than the investigational study treatment start date 
year value, the CM started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JANYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).
If the CM start date year value is equal to the investigational study treatment start date 
year value:
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior to treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date.
CM end date imputation
If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM 
end date is set to NULL.


Novartis
For business use only
Page 26
SAP
CRFB002ADE27
Else, if the CM end date month is missing, the imputed end date should be set to the 
earliest of the (treatment follow up period date, 31DECYYYY, date of death).
If the CM end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death).
If the imputed CM end date is less than the existing CM start date, use the CM start date 
as the imputed CM end date.
Other imputations
Other missing baseline data will not be imputed.
Efficacy variables and populations for analysis
Table 5-1 describes the primary and secondary efficacy endpoints with the respective methods 
and sets for analysis. 
Table 5-1
Primary and secondary efficacy endpoints
Table 
Variable
Analysis
Type
Method
Population 
(method of 
imputation)
Missing VEGF-A level 
baseline values 
imputation
Primary
AUC of 
systemic 
VEGF-A 
levels
Mean AUC 
systemic 
VEGF-A 
levels from 
Day 1 to 
week 12 
(visit 10)
Main
ANCOVA1
PPS 
(observed 
data)
Mean value of non-
missing baseline 
VEGF-A level from all 
the patients with values
Sensitivity
ANCOVA1
FAS (observed 
data)
Mean value of non-
missing baseline 
VEGF-A level from all 
the patients with values
Sensitivity
ANCOVA2
PPS 
(observed 
data)
Mean value of non-
missing baseline 
VEGF-A level from all 
the patients with values
Sensitivity
ANCOVA1
PPS 
(observed 
data)
No imputation
Secondary
AUC of 
systemic 
VEGF-A 
levels
Mean AUC 
systemic 
VEGF-A 
levels from 
week 12 
(visit 10) to 
week 24
(visit 16)
Main
ANCOVA1
PPS 
(observed 
data)
Mean value of non-
missing baseline 
VEGF-A level from all 
the patients with values
Main
ANCOVA1
FAS (observed 
data)
Mean value of non-
missing baseline 
VEGF-A level from all 
the patients with values
1 The model includes the systemic VEGF-A baseline level as a linear covariate and the following 
categorical variables: treatment,  center
2 The model includes the systemic VEGF-A baseline level as a linear covariate and the following 


Novartis
For business use only
Page 27
SAP
CRFB002ADE27
Table 
Variable
Analysis
Type
Method
Population 
(method of 
imputation)
Missing VEGF-A level 
baseline values 
imputation
Primary
categorical variables: treatment,  center, gender
SAS code for analysis
SAS code for ANCOVA analysis
The ANCOVA model will contain ‘treatment’ and ‘center’ as categorical variables, and 
‘baseline systemic VEGF-A’ as continuous. 
For the appropriate treatment difference, the treatments should be sorted or coded 
appropriately before using this model.
The ANCOVA analysis will be performed using SAS procedure PROC MIXED as below. 
Note that for this illustrative example:
the data are stored in the file data_set
treatmentvar = treatment variable
responsevar = dependent variable
stratavar = stratification variable 
bsl = baseline value of the responsevar 
alpha = significance level (i.e. 0.05 produces two-sided 95% CI)
control = control group 
PROC MIXED DATA = <data_set>;
CLASS <stratavar> <treatmentvar>;
MODEL <responsevar> = <stratavar> <treatmentvar> <bsl>;
LSMEANS <treatmentvar> / PDIFF = all CL alpha = <alpha> OM;
RUN;
Clinically notable laboratory values and vital signs
Table 5-2
Vital signs critical values
Variable
Type of 
abnormality
Criterion
Systolic blood 
pressure (mmHg)
High
Either >180 with an increase from baseline > 30 or > 200 
absolute 
Low
Either < 90 with a decrease from baseline > 30 or < 75 
absolute 
Diastolic blood 
pressure (mmHg)
High
Either >105 with an increase from baseline > 20 or > 115 
absolute 
Low
Either < 50 with a decrease from baseline > 20 or < 40 
absolute 
Pulse rate (bpm)
High
Either > 120 with an increase from  baseline > 25 or > 130 


Novartis
For business use only
Page 28
SAP
CRFB002ADE27
Variable
Type of 
abnormality
Criterion
absolute
Low
Either < 50 with a decrease from baseline > 30 or < 40 
absolute 
Rule of exclusion criteria of analysis sets 
Table 5-3
Protocol Deviation categories used
PD Category
PD Code
Patient did not satisfy inclusion criteria
I
Patient met exclusion criteria
E
Patient received the wrong treatment or incorrect dose
S
Patient met compliance violation (unblinding)
C
Patient participated in treatment relevant visits out of schedule
T
Patient had missing values in the primary variable
P
Patient developed withdrawal criteria during the study, but not withdrawn
D
Patient took an excluded concomitant medication
M
Others
O
Table 5-4
Protocol deviations that cause subject to be excluded
Deviation 
code
Text description
Action for analysis
S1
In case of treatment group 1 & 2: Application of study drug from the 
wrong treatment arm group in study eye at visit 2, 6, or 8
Exclude from PPS
S6
The interval between two intravitral injections should not be shorter 
than 28 days
Exclude from PPS
if difference is <= 
23 days
Reference
Avery R (2013) Comparison of Systemic Pharmacokinetics Post-Anti-VEGF Intravitreal 
Injections of Ranibizumab, Bevacizumab and Aflibercept. Data presented at ASRS Annual 
Meeting, Toronto CA, 25th August 2013. 
Carneiro AM, Costa R, Falcão MS et al. (2012) Vascular endothelial growth factor plasma 
levels before and after treatment of neovascular age-related macular degeneration with 
bevacizumab or ranibizumab. Acta Ophthalmol, vol. 90 (1), p. e25-30. 
Chakravarthy U, Harding SP, Rogers CA et al. (2012) Ranibizumab versus bevacizumab to 
treat neovascular age-related macular degeneration: one-year findings from the IVAN 
randomized trial. Ophthalmology, vol. 119 (7), p. 1399-411. 
Chakravarthy U, Harding SP, Rogers CA et al. (2013) Alternative treatments to inhibit VEGF 
in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised 
controlled trial. The Lancet, vol. 382 (9900), p. 1258-67. 


Novartis
For business use only
Page 29
SAP
CRFB002ADE27
Koch GG, Tangen CM, Jung J-W and Amara IA (1998) Issues for covariance analysis of 
dichotomous and ordered categorical data from randomized clinical trials and non-parametric 
strategies for addressing them. Statistics in Medicine, vol 17, p. 1863-92.
Zehetner C, Kirchmair R, Huber S et al. (2013) Plasma levels of vascular endothelial growth 
factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in 
patients with age-related macular degeneration, and in patients with diabetic macular oedema. 
Br J Ophthalmol, vol. 97 (4), p. 454-9.
References are available upon request.