A Real-world, Prospective, Multi-center, Open-label, Phase IV Clinical Study to Evaluate the Safety and Effectiveness of Intravitreal Injections (IVI) of Brolucizumab in Patients With Neovascular Age-related Macular Degeneration (nAMD)
Phase: PHASE4
Conditions: Neovascular Age-related Macular Degeneration (nAMD)
Sponsor: Novartis Pharmaceuticals

Official Title:  A Real-world, Prospective, Multi-center, Open-label, Phase IV Clinical Study to 
Evaluate  
Evaluate the Safety and Effectiveness of Intravitreal Injections (IVI) of 
Brolucizumab in Patients With Neovascular Age-related Macular Degeneration 
(nAMD)
NCT Number: 
 NCT05269966 
Document Date: Protocol (Version 2.0): 06-May-2021

Page 1 
Interventional Study Protocol V 0.2 
Brolucizumab/CRTH258AIN01 
Medical Affairs 
Interventional Study Protocol (PASS) 
Protocol number: CRTH258AIN01 
A real-world, prospective, multi-center, open-label, phase IV clinical study to evaluate 
the safety and effectiveness of intravitreal injections (IVI) of brolucizumab in patients 
with neovascular age-related macular degeneration (nAMD) 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Interventional Study protocol for primary data collection Version 3.0 dated 14-August-2017
Authors: 
Dr.
 
Dr.
 
Document type: 
Interventional clinical study protocol 
Version number: 
Version 0.2  
Release date: 
6th May 2021 

Novartis 
Confidential 
Page 2 
Interventional study protocol V 0.2 
Brolucizumab/CRTH258AIN01  
Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 4 
List of tables........................................................................................................................ 4 
List of abbreviations ............................................................................................................ 5 
1 
Responsible parties ....................................................................................................... 7 
2 
Abstract........................................................................................................................ 7 
3 
Amendments and updates............................................................................................ 12 
4 
Milestones .................................................................................................................. 12 
5 
Rationale and background ........................................................................................... 12 
6 
Research question and objectives ................................................................................ 13 
6.1 
Primary Objective ............................................................................................ 14 
6.2 
Secondary Objectives....................................................................................... 14 
7 
Research methods ....................................................................................................... 14 
7.1 
Study design .................................................................................................... 14 
7.1.1 
Primary Endpoint ............................................................................. 14 
7.1.2 
Secondary Endpoints ........................................................................ 15 
7.2 
Setting............................................................................................................. 15 
7.2.1 
Inclusion criteria .............................................................................. 16 
7.2.2 
Exclusion criteria ............................................................................. 16 
7.3 
Variables ......................................................................................................... 16 
7.3.1 
Demography and Baseline characteristics.......................................... 16 
7.3.2 
Physical examination........................................................................ 17 
7.3.3 
Vital signs........................................................................................ 17 
7.3.4 
Effectiveness variables ..................................................................... 17 
7.3.5 
Safety variables ................................................................................ 17 
7.3.6 
Data sources..................................................................................... 18 
7.3.7 
Data collection schedule ................................................................... 18 
7.4 
Study size ........................................................................................................ 20 
7.5 
Data management ............................................................................................ 20 
7.5.1 
Data collection ................................................................................. 20 

Novartis 
Confidential 
Page 3 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.5.2 
Database management and quality control ......................................... 20 
7.6 
Data analysis ................................................................................................... 21 
7.6.1 
General statistical considerations ...................................................... 21 
7.6.2 
Analysis sets .................................................................................... 21 
7.6.3 
Patient demography and other baseline characteristics ....................... 21 
7.6.4 
Treatments ....................................................................................... 22 
7.6.5 
Safety and Effectiveness analysis ...................................................... 22 
7.7 
Quality control................................................................................................. 23 
7.7.1 
Data quality management ................................................................. 23 
7.7.2 
Data recording and document retention ............................................. 23 
7.7.3 
Site monitoring ................................................................................ 23 
7.8 
Limitations of the research methods ................................................................. 24 
7.9 
Other aspects ................................................................................................... 24 
8 
Protection of human subjects....................................................................................... 25 
8.1 
Regulatory and ethical compliance ................................................................... 25 
8.2 
Informed consent procedures............................................................................ 25 
8.3 
Responsibilities of the Investigator and IRB/IEC .............................................. 26 
9 
Safety Monitoring ....................................................................................................... 26 
9.1 
Adverse events (AE) ........................................................................................ 26 
9.2 
Serious Adverse Events (SAEs)........................................................................ 28 
9.2.1 
Notification of serious adverse events to Novartis Pharmaceuticals 
Patient Safety ................................................................................... 29 
9.2.2 
Reporting procedures ....................................................................... 29 
10 Plans of disseminating and communicating study results .............................................. 29 
11 References.................................................................................................................. 30 
 
 
 

Novartis 
Confidential 
Page 4 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
List of figures 
None 
List of tables 
Table 1-1 
Responsible parties............................................................................. 7 
Table 4-1 
Planned date of study milestones....................................................... 12 
Table 7-1 
Data collection ................................................................................. 19 
 
 
 

Novartis 
Confidential 
Page 5 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
List of abbreviations 
AE 
 
Adverse Event 
AMD  
Age-related Macular Degeneration 
ANOVA 
Analysis Of Variance 
ATC   
Anatomical Therapeutic Chemical 
ATE 
 
Arterial Thromboembolic Events 
BCVA  
Best Corrected Visual Acuity 
BL  
 
Baseline 
CI 
 
Confidence Interval 
CNV   
Choroidal Neo Vascularization 
CRF 
 
Case Report/Record Form 
CRO  
Contract Research Organization 
CST 
 
Central Subfield Thickness 
DBP  
Diastolic Blood Pressure 
DS&E  
Drug Safety and Epidemiology 
eCRF  
electronic Case Report/Record Form 
EMA   
European Medicines Agency 
FA 
 
Fluorescein Angiography 
FAS 
 
Full Analysis Set 
GCP 
 
Good Clinical Practice 
HA 
 
Health Authorities 
ICH 
 
International Conference on Harmonization 
ICMJE  
International Committee of Medical Journal Editors 
IEC 
 
Independent Ethics Committee 
IN 
 
Investigator Notification 
IOP 
 
Intra-ocular Pressure 
IRB 
 
Institutional Review Board 
IVI 
 
Intravitreal Injection 
IVT 
 
Intravitreal 
LOCF  
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 

Novartis 
Confidential 
Page 6 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
nAMD  
Neovascular Age-related Macular Degeneration 
OCT  
Optical Coherence Tomography 
PI 
 
Prescribing Information 
REB 
 
Research Ethics Board 
RPE 
 
Retinal Pigment Epithelium 
SAE 
 
Serious Adverse Event 
SBP 
 
Systolic Blood Pressure 
scFv 
 
Single-Chain fragment variable 
SD 
 
Standard Deviation 
SmPC  
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
USFDA 
United States Food and Drug Administration 
VA 
 
Visual Acuity 
VEGF  
Vascular Endothelial Growth Factor 
VEGFR1 
Vascular Endothelial Growth Factor Receptor 1 
VEGFR2 
Vascular Endothelial Growth Factor Receptor 2 
 
 
WHO  
World Health Organization 
WHO-DRL 
World Health Organization Drug Reference List 
 
 
 

Novartis 
Confidential 
Page 7 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
1 
Responsible parties 
Table 1-1 
Responsible parties 
Role 
Person 
Main protocol author(s) Dr.
 
Dr.
 
2 
Abstract 
A real-world, prospective, multi-center, open-label, phase IV clinical study to evaluate the 
safety and effectiveness of intravitreal injections (IVI) of brolucizumab in patients with 
neovascular age-related macular degeneration (nAMD). 
Version and date 
V 0.2 
Name and affiliation of the main authors 
Dr.
 
Dr. 
 
Novartis Healthcare Private Limited (NHPL, India) 
Rationale and background 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
affecting 10%-13% of individuals over the age of 65 in North America, Europe, and Australia 
(Smith 2001, Rein 2009, Kawasaki 2010). Genetic, environmental, and health factors play an 
important role in the pathogenesis of the disease. 
AMD is classified into two clinical subtypes: the non-neovascular (atrophic) or dry form and 
the neovascular (exudative) or wet form (Ferris 1984, Lim 2012, Miller 2013). Neovascular 
age-related macular degeneration (nAMD) is characterized by the growth of abnormal new 
blood vessels (neovascularization) under the retinal pigment epithelium (RPE) or sub-retinal 
space from the subjacent choroid, termed choroidal neovascularization (CNV) (Ferris, 1984). 
These newly formed vessels have an increased likelihood to leak blood and serum, damaging 
the retina by stimulating inflammation and scar tissue formation. This damage to the retina 
results in progressive, severe, and irreversible vision loss (Shah 2007, Shah 2009). Without 
treatment, most affected eyes will have poor central vision (20/200) within 12 months (Blinder 
2003). Although the neovascular form of the disease is only present in about 10% of all AMD 
cases, it accounted for approximately 90% of the severe vision loss from AMD prior to the 
introduction of anti-vascular endothelial growth factor (VEGF) treatments (Ferris 1983, 
Sommer 1991, Wong 2008). 
VEGF has been shown to be elevated in patients with neovascular AMD and is thought to play 
a key role in the neovascularization process (Spilsbury 2000). The use of intravitreal (IVT) 
pharmacotherapy targeting VEGF has significantly improved visual outcomes in patients with 
neovascular age-related macular degeneration (Bloch 2012, Campbell 2012). Anti-VEGF 

Novartis 
Confidential 
Page 8 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
treatments, such as ranibizumab (LUCENTIS) and aflibercept (EYLEA), inhibit VEGF 
signaling pathways and have been shown to halt the growth of neovascular lesions and resolve 
retinal edema. 
Brolucizumab, formerly known as ESBA1008, is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of VEGF with a molecular weight of ~26 kDa that is being developed for 
the treatment of CNV associated with neovascular AMD. It is an inhibitor of VEGF-A and 
works by binding to the receptor binding site of the VEGF-A molecule, thereby preventing the 
interaction of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of endothelial 
cells. Increased levels of signaling through the VEGF pathway are associated with pathologic 
ocular angiogenesis and retinal edema. Inhibition of the VEGF pathway has been shown to 
inhibit the growth of neovascular lesions and resolve retinal edema in patients with nAMD 
(Nguyen 2020, Brolucizumab Prescribing Information).  
Two pivotal phase 3 trials (HAWK and HARRIER) with similar designs, compared 
brolucizumab with aflibercept to treat nAMD in 1817 patients with untreated, active CNV due 
to AMD in the study eye. Brolucizumab was non-inferior to aflibercept in visual function at 
Week 48, and more than 50% of brolucizumab 6 mg-treated eyes were maintained on 12 weekly 
dosing through Week 48. Greater central subfield thickness (CST) reductions from baseline to 
Week 48 were observed with brolucizumab 6 mg versus aflibercept. Anatomic retinal fluid 
outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally 
similar with brolucizumab and aflibercept (Dugel 2020).  
Currently, the drug is approved by the USFDA, the European Medicines Agency (EMA), and 
the Drugs Controller General of India (DCGI). This study is being conducted as part of the post-
marketing regulatory requirements in India.  
The purpose of this study is to generate additional safety and effectiveness data in a larger 
nAMD patient population in India that more closely resembles the real-world population 
intended to be treated with brolucizumab.  
The final data from this study would be compared descriptively with the corresponding data 
from Hawk and Harrier (Dugel 2020).  
Research question and objectives  
Primary Objective: 
1. To evaluate ocular & non-ocular safety of intravitreal brolucizumab in real-world 
patients with nAMD.  
Primary Endpoints:  
Incidence and characteristics of treatment-emergent adverse events during the 56 weeks of 
treatment with brolucizumab. 
Secondary Objectives:  
1. To evaluate the effectiveness of brolucizumab in the management of nAMD in terms of 
change in best-corrected visual acuity (BCVA) from baseline to Week 56. 

Novartis 
Confidential 
Page 9 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
2. Characterize the number of anti-VEGF injections, number of non-injection visits, and 
total number of visits during the 56 weeks of treatment with brolucizumab.  
3. Estimate the percentage (%) of patient eyes with anti-VEGF injection intervals q8w and 
q12w during the 56 weeks of treatment with brolucizumab.  
4. Estimate effect of brolucizumab on fluid from baseline to week 16 and week 56. 
5. Estimate effect of brolucizumab on central subfield thickness (CST) from baseline to 
week 16 and week 56. 
Secondary Endpoints 
1.1  
Mean change in BCVA from baseline to week 16 and week 56 as measured by Early 
Treatment Diabetic Retinopathy Study (ETDRS) letters.  
1.2  
Percentage (%) of patient eyes with gain in BCVA of 15/10/5 ETDRS letters or more 
from baseline to week 16 and week 56.  
1.3  
Percentage (%) of patient eyes with loss in BCVA of 15/10/5 ETDRS letters or more 
from baseline to week 16 and week 56. 
2.  
Number of anti-VEGF injections, non-injection visits, and total number of visits 
during the 56 weeks of treatment with brolucizumab. 
3.1  
Percentage (%) of patient eyes with at least one duration of interval between 
injections ≥ 8 weeks but <12 weeks. 
3.2  
Percentage (%) of patient eyes with at least one duration of interval between 
injections ≥ 12 weeks. 
4.1  
Absence of intra-retinal fluid from baseline to week 16 and week 56. 
4.2  
Absence of sub-retinal fluid from baseline to week 16 and week 56.  
5. 
Estimate CST change from baseline (in μm) to week 16 and at week 56. 
Study design  
This is a prospective, multi-center, open-label, interventional phase IV clinical study. The study 
treatment i.e. brolucizumab will be prescribed in terms of the marketing authorization; the 
assignment of the patient to the therapy will be decided within the current practice and the 
medical indication, and will clearly be separated from the decision to include the patient in the 
study.  
All patients with nAMD who are planned to be treated with brolucizumab and have provided 
informed consent may be enrolled in this study. The treatment period for each patient will be 
56 weeks after the start of brolucizumab treatment. Study visits will be scheduled at week 4, 
week 8, week 16, and thereafter at intervals of 8 weeks or 12 weeks after disease activity 
assessment at week 16. If the investigators require more frequent follow-up visits, it can be 
done according to their discretion and clinical judgment. Any patient who suffers from intra-
ocular inflammation (IOI) during the study period would not be re-challenged with 
brolucizumab.  

Novartis 
Confidential 
Page 10 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Data originating from assessments and evaluations performed will be collected from the 
patient's medical records at Baseline (BL), i.e. start of brolucizumab treatment, week 4, week 
8, week 16, week 20, week 24, week 32, week 40, week 44, week 48 and at week 56. 
Setting and study population 
The study plans to enroll a total of 105 patients in 10 centers.  
Inclusion criteria: 
1. Female or male, treatment naïve patient with ≥50 years of age, with neovascular age-
related macular degeneration (nAMD). 
2. Patient or legally acceptable representative (LAR) willing to voluntarily provide signed 
informed consent for participation in the study. 
Note: In case where both eyes are affected, data of only one eye [‘study eye’] will be recorded. 
selection of the eye to be considered for the purpose of the study [referred to as ‘study eye’] 
will be as per the Investigator’s discretion. 
Exclusion criteria: 
Patients fulfilling any of the following criteria are not eligible for this study: 
1. Patient having other eye diseases that could compromise the visual acuity (VA). 
2. Patient with existing or suspected ocular or periocular infection in the study eye.  
3. Patient with an existing intraocular inflammation (IOI). 
4. Patient with uncontrolled glaucoma defined as intraocular pressure > 25 mmHg despite 
treatment with anti-glaucoma medication, or according to Investigator’s judgment. 
5. Patient who has undergone intraocular surgery within 3 months prior to enrollment in 
this study 
6. Patient having scar, fibrosis and atrophy involving the center of the fovea in the study 
eye. 
Variables 
 Demographic and baseline characteristics 
 Physical examination 
 Vital signs 
 Effectiveness variables 
o Visual acuity (VA) 
o Number of brolucizumab injections for treatment during the study duration 
o q8w and q12w injection interval 
o Intra-retinal fluid (IRF) and Sub-retinal fluid (SRF) 
o Central subfield thickness (CST) 
 Safety variables 
o Adverse events (AEs) and serious adverse events (SAEs) reporting 
o any significant changes in the vital signs and/or physical examination parameters 

Novartis 
Confidential 
Page 11 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Data sources 
Information on brolucizumab administration since treatment start will be recorded in the Case 
Report/Case Record Form (CRF). All concomitant medications including the reason for 
prescribing the medication and the start and end dates will be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
Initiation of the participating sites will be performed by Novartis and/or a designated Contract 
Research Organization (CRO).  
Sites enrolling subjects in this study will record data on eCRFs provided by Novartis. A 
designated CRO will capture, check, store and analyze the data. 
Concomitant or prior medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Reference List. Medical history/current medical conditions 
and adverse events will be coded using the MedDRA terminology. 
Study size  
The sample size of this interventional study will be 105 considering 10% dropouts/lost to 
follow-up. The actual estimated sample size is 95. 
Data analysis 
All analyses will be performed by Novartis and/or a designated CRO after all enrolled patients 
complete the 56 weeks study period. 
Milestones 
Planned dates of study milestones: 
Primary data collection for this interventional study will be as mentioned below: 
Planned protocol finalization date: 6th May 2021 
Planned start of data collection (FPFV): 01 May 2022 
Planned end of data collection (LPLV): 01 Dec 2023 
Interim safety report: Quarterly 
Planned Interventional study Report date (interim/final report): 01 June 2024 
Planned first publication date: 01 Jul 2025 
 

Novartis 
Confidential 
Page 12 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
3 
Amendments and updates 
None 
4 
Milestones 
Table 4-1 
Planned date of study milestones 
Milestone 
Planned date 
Start of data collection 
01 May 2022 
End of data collection 
01 Dec 2023 
Interim safety report 
Quarterly  
Final report of study results 
01 June 2024  
5 
Rationale and background 
Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people 
affecting 10%-13% of individuals over the age of 65 in North America, Europe, and Australia 
[1-3]. Genetic, environmental, and health factors play an important role in the pathogenesis of 
the disease. 
Neovascular AMD is classified into two clinical subtypes: the non-neovascular (atrophic) or 
dry form and the neovascular (exudative) or wet form [4-6]. Neovascular age-related macular 
degeneration (nAMD) is characterized by the growth of abnormal new blood vessels 
(neovascularization) under the retinal pigment epithelium (RPE) or sub-retinal space from the 
subjacent choroid, termed choroidal neovascularization (CNV) [5]. These newly formed vessels 
have an increased likelihood to leak blood and serum, damaging the retina by stimulating 
inflammation and scar tissue formation. This damage to the retina results in progressive, severe, 
and irreversible vision loss [7, 8]. Without treatment, most affected eyes will have poor central 
vision (20/200) within 12 months [9]. Although the neovascular form of the disease is only 
present in about 10% of all AMD cases, it accounted for approximately 90% of the severe vision 
loss from AMD prior to the introduction of anti-vascular endothelial growth factor (VEGF) 
treatments [5, 10, 11].  
VEGF has been shown to be elevated in patients with neovascular AMD and is thought to play 
a key role in the neovascularization process [12]. The use of intravitreal (IVT) pharmacotherapy 
targeting VEGF has significantly improved visual outcomes in patients with neovascular age-
related macular degeneration [13,14]. Anti-VEGF treatments, such as ranibizumab and 
aflibercept inhibit VEGF signaling pathways and have been shown to halt the growth of 
neovascular lesions and resolve retinal edema. 
Brolucizumab, formerly known as ESBA1008, is a humanized single-chain Fv (scFv) antibody 
fragment inhibitor of VEGF with a molecular weight of ~26 kDa that is being developed for 
the treatment of CNV associated with nAMD. It is an inhibitor of VEGF-A and works by 
binding to the receptor binding site of the VEGF-A molecule, thereby preventing the interaction 
of VEGF-A with its receptors VEGFR1 and VEGFR2 on the surface of endothelial cells. 

Novartis 
Confidential 
Page 13 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Increased levels of signaling through the VEGF pathway are associated with pathologic ocular 
angiogenesis and retinal edema. Inhibition of the VEGF pathway has been shown to inhibit the 
growth of neovascular lesions and resolve retinal edema in patients with nAMD. There is a 
potential risk of arterial thromboembolic events (ATE) following intravitreal use of VEGF 
inhibitors [15,16].  
Two pivotal phase 3 trials (HAWK and HARRIER) with similar designs, compared 
brolucizumab with aflibercept to treat nAMD in 1817 patients with untreated, active CNV due 
to AMD in the study eye. Brolucizumab was non-inferior to aflibercept in visual function at 
Week 48:each brolucizumab arm demonstrated non inferiority to aflibercept in best-corrected 
visual acuity (BCVA) change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 
mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 
mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 
50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 
(56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer 
brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 
34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield 
thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus 
aflibercept in HAWK (LS mean -172.8 μm vs. -143.7 μm; P = 0.001) and HARRIER (LS mean 
-193.8 μm vs. -143.9 μm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizuma b 
over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and 
aflibercept [17]. 
Currently, brolucizumab is approved by the USFDA, the European Medicines Agency (EMA), 
and the Drugs Controller General of India (DCGI). This multi-center, open-label, prospective, 
interventional, phase IV study is being conducted as part of the post-marketing regulatory 
requirements in India.  
This study will evaluate the safety and effectiveness of intravitreal injections (IVI) of 
brolucizumab in patients with neovascular age-related macular degeneration (nAMD) over 56 
weeks.  
The purpose of this study is to generate additional safety and effectiveness data in a larger 
nAMD patient population in India that more closely resembles the real-world population 
intended to be treated with brolucizumab.  
It is expected that this study will provide the real-world determinants of clinical response to 
brolucizumab. The final data of this study would be compared descriptively with the 
corresponding data from the Hawk and Harrier studies [17].  
6 
Research question and objectives 
The purpose of this study is to generate additional safety and effectiveness data in Indian nAMD 
patients that more closely resemble the real-world population intended to be treated with 
brolucizumab.  
This study is being conducted as part of the post-marketing regulatory commitment to the Indian 
Health authority.  

Novartis 
Confidential 
Page 14 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
6.1 
Primary Objective 
1. To evaluate ocular & non-ocular safety of intravitreal brolucizumab in real-world 
patients with nAMD.  
6.2 
Secondary Objectives 
1. To evaluate the effectiveness of brolucizumab in the management of nAMD in terms of 
change in best-corrected visual acuity (BCVA) from baseline to Week 56. 
2. Characterize the number of anti-VEGF injections, number of non-injection visits, and 
total number of visits during the 56 weeks of treatment with brolucizumab.  
3. Estimate the percentage (%) of patient eyes with anti-VEGF injection intervals q8w and 
q12w during the 56 weeks of treatment with brolucizumab.  
4. Estimate effect of brolucizumab on fluid from baseline to week 16 and week 56. 
5. Estimate effect of brolucizumab on central subfield thickness (CST) from baseline to 
week 16 and week 56. 
7 
Research methods 
7.1 
Study design 
This is a prospective, multi-center, open-label, interventional phase IV clinical study. The study 
treatment i.e. brolucizumab will be prescribed in terms of the marketing authorization; the 
assignment of the patient to the therapy will be decided within the current practice and the 
medical indication, and will clearly be separated from the decision to include the patient in the 
study.  
All patients with nAMD who are planned to be treated with brolucizumab and have provided 
informed consent may be enrolled in this study. The treatment period for each patient will be 
56 weeks after the start of brolucizumab treatment. Study visits will be scheduled at week 4, 
week 8, week 16, and thereafter at intervals of 8 weeks or 12 weeks after disease activity 
assessment at week 16. If the investigators require more frequent follow-up visits, it can be 
done according to their discretion and clinical judgment. The study drug will be provided free 
of cost to the patients in the study. Any patient who suffers from intra-ocular inflammation 
(IOI) during the study period would not be re-challenged with brolucizumab.  
Data originating from assessments and evaluations performed will be collected from the 
patient's medical records at Baseline (BL), i.e. start of brolucizumab treatment, week 4, week 
8, week 16, week 20, week 24, week 32, week 40, week 44, week 48 and at week 56. 
7.1.1 
Primary Endpoint 
Incidence and characteristics of treatment-emergent adverse events during the 56 weeks of 
treatment with brolucizumab. 

Novartis 
Confidential 
Page 15 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.1.2 
Secondary Endpoints 
1.1  
Mean change in BCVA from baseline to week 16 and week 56 as measured by Early 
Treatment Diabetic Retinopathy Study (ETDRS) letters.  
1.2  
Percentage (%) of patient eyes with gain in BCVA of 15/10/5 ETDRS letters or more 
from baseline to week 16 and week 56.  
1.3  
Percentage (%) of patient eyes with loss in BCVA of 15/10/5 ETDRS letters or more 
from baseline to week 16 and week 56. 
2.  
Number of anti-VEGF injections, non-injection visits, and total number of visits during 
the 56 weeks of treatment with brolucizumab. 
3.1  
Percentage (%) of patient eyes with at least one duration of interval between injections 
≥ 8 weeks but <12 weeks. 
3.2  
Percentage (%) of patient eyes with at least one duration of interval between injections 
≥ 12 weeks. 
4.1  
Absence of intra-retinal fluid from baseline to week 16 and week 56. 
4.2  
Absence of sub-retinal fluid from baseline to week 16 and week 56.  
5. 
Estimate CST change from baseline (in μm) to week 16 and at week 56. 
7.2 
Setting 
The study population will consist of adult male and female outpatients aged 50 years and above, 
diagnosed with nAMD for whom the treating physician (Investigator) prescribes treatment with 
brolucizumab 6 mg injection in adherence with the local Summary of Product Characteristics 
(SmPC) or Prescribing Information (PI). The treatment with brolucizumab should not have been 
be prescribed for the purpose of entering a patient in this interventional study, but solely based 
on the clinical judgment of the treating physician. Patients will be considered eligible for this 
study only after the decision to prescribe brolucizumab has been made as per the treating 
physician’s clinical judgement. The patients should have provided voluntary informed consent 
to participate in the study.  
Brolucizumab 6 mg will be administered by IVT injection as per the Prescribing information 
(PI) and in line with the treating physician’s clinical judgement. Patients will receive loading 
doses of brolucizumab at Day 0/Visit 1, Week 4/Visit 2 and Week 8/Visit 3. After the loading 
doses, at Week 16, disease activity assessment (DAA) will be performed based on BCVA and 
OCT to assess whether the patient will require q8w or q12w dosing. 
Patients who are scheduled for q8w dosing with brolucizumab will receive injections at weeks 
16, 24, 32, 40, 48.  
Patients who are scheduled for q12w dosing of brolucizumab will receive injections at weeks 
20, 32, and 44.  
DAA will be conducted as per the q8w and q12w dosing administration. Allocation and re-
allocation to q8w/q12w dosing regimen will be as per Investigator’s discretion. 

Novartis 
Confidential 
Page 16 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.2.1 
Inclusion criteria 
1. Female or male, treatment naïve patient with ≥50 years of age, with neovascular age-
related macular degeneration (nAMD). 
2. Patient or legally acceptable representative (LAR) willing to voluntarily provide signed 
informed consent for participation in the study. 
Note: In case where both eyes are affected, data of only one eye [‘study eye’] will be recorded. 
Selection of the eye to be considered for the purpose of the study [referred to as ‘study eye’] 
will be as per the Investigator’s discretion. 
7.2.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for this study: 
1. Patient having other eye diseases that could compromise the VA. 
2. Patient with existing or suspected ocular or periocular infection in the study eye.  
3. Patient with an existing intraocular inflammation (IOI). 
4. Patient with uncontrolled glaucoma defined as intraocular pressure > 25 mmHg despite 
treatment with anti-glaucoma medication, or according to Investigator’s judgment. 
5. Patient who has undergone intraocular surgery within 3 months prior to enrollment in 
this study. 
6. Patient having scar, fibrosis and atrophy involving the center of the fovea in the study 
eye. 
7.3 
Variables 
7.3.1 
Demography and Baseline characteristics  
Patient demographics, medical history will be done at the first visit at the time of screening ( 
 
 
 

Novartis 
Confidential 
Page 17 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Table 7-1). Patient demographic and baseline characteristic data taken at study entry will 
include: date of birth, gender, race, ethnicity, weight and height, smoking history, history of 
ocular disease (diagnosis of nAMD and any other ocular conditions), other relevant medical 
histories (significant medical conditions and surgical events), treatment for nAMD received in 
the 12 months prior to study entry. 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
class and preferred term according to the WHO-DRL dictionary. 
7.3.2 
Physical examination 
The physical exam will consist of a routine evaluation of organ systems e.g., ears, eyes, nose, 
throat, neck, lymph nodes, lungs, heart, abdomen, skin/extremities, neurological, and 
musculoskeletal systems. 
Information for all physical examinations will be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to initiating treatment with 
brolucizumab 6 mg injection must be included in the appropriate section of the CRF. 
7.3.3 
Vital signs 
Vital signs including blood pressure (BP), heart rate, systolic (SBP) and diastolic blood pressure 
(DBP) will be measured when the patient has been sitting for approximately five minutes. If an 
automated blood pressure device is used, it should be calibrated according to the manufacturer’s 
guidelines.  
7.3.4 
 Effectiveness variables 
1. Visual acuity (VA) in ETDRS letter 
2. Number of brolucizumab injections for treatment during study duration 
3. q8w and q12w injection interval 
4. Intra-retinal fluid (IRF) and Sub-retinal fluid (SRF) 
5. Central subfield thickness (CST) 
7.3.5 
Safety variables 
Adverse events (AEs) and serious adverse events (SAEs) reporting 
Treatment-emergent changes in any of the ocular parameters, which meet the definition of an 
Adverse Event (serious and non-serious), will be recorded in the appropriate section of the CRF. 
Any significant changes in the vital signs and/or physical examination parameters observed 
after first administration of brolucizumab which meet the definition of an Adverse Event will 
be recorded in the appropriate section of the CRF. 
Exposure of interest 
Exposure to study medication from start to end of treatment within this interventional study. 
The number (%) of patients who discontinue prematurely prior to 56 weeks with including the 

Novartis 
Confidential 
Page 18 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
reasons for discontinuation. Furthermore, the number of injections will be presented for the 
total study period. 
7.3.6 
Data sources 
Information on brolucizumab administration since treatment start will be recorded in the Case 
Report/Case Record Form (CRF). All concomitant medications including the reason for 
prescribing the medication and the start and end dates will be recorded on the concomitant 
medications/significant non-drug therapies CRF. 
Initiation of the participating sites will be performed by Novartis and/or a designated Contract 
Research Organization (CRO).  
Sites enrolling subjects in this study will record data on eCRFs provided by Novartis. A 
designated CRO will capture, check, store and analyze the data. 
Concomitant or prior medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Reference List. Medical history/current medical conditions 
and adverse events will be coded using the MedDRA terminology. 
7.3.7 
Data collection schedule 
Data originating from routine patient visits and assessments at study time points (Baseline, i.e. 
start of brolucizumab treatment, and approximately week 4, week 8, week 16, week 20, week 
24, week 32, week 40, week 44, week 48 and at week 56 post-initiation of treatment/or 
discontinuation of treatment) and safety data (AEs and SAEs, see Section 8) from any time 
point during the duration of the study will be recorded for the purpose of this study. Data will 
be collected only on the eye treated with brolucizumab and if both eyes are treated with 
brolucizumab, the data from one eye (study eye) will be recorded. The selection of eye (study 
eye) will be as per discretion of the Investigator at the time of enrolment in this study. 
Participation in this prospective interventional study and confirmation of patient consent to 
collect and use patient data will be documented using an informed consent form by the site staff 
on or before the baseline visit. A copy of this signed document will be given to the patient and 
the original will remain in the patient’s records. 
Each patient is uniquely identified in the study by a combination of the Investigator’s center 
number and a patient number. The center number is assigned by Novartis (or designee), the 
patient number is assigned 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, and so forth). Once 
assigned to a patient, the patient number will not be reused. 
 
 
 

Novartis 
Confidential 
Page 19 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Table 7-1 
Data collection 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Time of visit 
[Week (Wk)] 
Wk 
0 
Wk 
4±1 
Wk 
8±1 
Wk 
16±1 
Wk 
20±1 
Wk 
24±1 
Wk 
32±1 
Wk 
40±1 
Wk 
44±1 
Wk 
48±1 
Wk 56 
(Follow-up) 
EOS 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
and Baseline 
Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination  
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
Brolucizumab 
X 
X 
X 
X* 
X# 
X* 
X*# 
X* 
X# 
X* 
 
BCVA 
X 
X 
X 
X*# 
X# 
X* 
X*# 
X* 
X# 
X* 
X 
IOP 
X 
X 
X 
X*# 
X# 
X* 
X*# 
X* 
X# 
X* 
X 
Fundus 
photography 
X 
 
 
X*# 
 
 
X*# 
 
 
 
X 
OCT 
X 
X 
X 
X* # 
X # 
X* 
X*# 
X* 
X # 
X* 
X 
Fluorescein 
Angiography 
(FA) 
X 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X*# 
X# 
X* 
X*# 
X* 
X# 
X* 
X 
* - q8w dosing 
# - q12w dosing 
Note: If the patient comes up at an unscheduled visit or more frequently, his/her BCVA should 
be measured as for the other visits.  

Novartis 
Confidential 
Page 20 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.4 
Study size 
The sample size of this interventional study is based on statistical consideration. The current 
study proposes to recruit 105 patients.  
For calculating sample size, safety results of the Phase 3 studies (Dugel 2020) were used. From 
these studies, the adverse event rate for relevant adverse events is assumed to be approximately 
1/100. 
The sample size was estimated empirically using 1000 replicates for each sample size between 
10 and 250 participants. The number of patients was selected to ensure at least a 90% probability 
that at least one of these rare adverse events will be observed in the study, which will allow the 
development of a comprehensive safety profile within the Indian population specifically. 
Estimated sample size: N = 95 
Additional 10% sample required for patient attrition over 56 weeks (dropouts/lost to follow-
up). 
Total sample size required: N = 105 
7.5 
Data management 
7.5.1 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the eCRFs using 
fully validated secure web-enabled software that conforms to US CFR 21 Part 11 requirements. 
Designated Investigator site staff will not be given access to the system until they have been 
trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated Investigator site staff. The Investigator must certify that 
the data entered into the eCRFs are complete and accurate. After database lock or when a site 
is closed, the Investigator will archive the copies of the patient data at the investigational site. 
The Principal Investigator is responsible for assuring that the data entered by the site personnel 
into the CRF is complete, accurate, and that entry and updates are performed in a timely manner. 
7.5.2 
Database management and quality control 
Novartis personnel or designated CRO personnel will review the data entered by study site staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator/site staff is required to respond 
promptly to queries and to make any necessary changes to the data.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List (WHO_DRL), which employs the ATC classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 

Novartis 
Confidential 
Page 21 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by Novartis. 
7.6 
Data analysis 
All analyses will be performed by Novartis or a designated CRO. 
An interim safety analysis will be performed for the first 50 patients and a quarterly interim 
safety report will be submitted to the Indian Regulatory Authority, as per their requirements. A 
complete analysis will be done after all enrolled patients complete the 56 weeks study period 
or discontinue the study prior to week 56.  
7.6.1 
General statistical considerations 
Summary statistics for continuous variables will include the number of observations (n), 
arithmetic mean, standard deviation (SD), minimum, lower quartile, median, upper quartile and 
maximum. Categorical variables will be presented with absolute and relative frequencies. In 
addition, key results will be presented with two-sided 95% confidence intervals and p-values 
for within-subject changes across time. 
If no post-baseline value is available for a parameter, then the patient will be removed from the 
analysis of this parameter. Otherwise, if at least one post-baseline value is available, missing 
values will be imputed by the last observation carried forward (LOCF) principle regardless of 
the reason for missing data. Apart from specific summaries and analyses described below, all 
CRF data will be listed. 
7.6.2 
Analysis sets 
The Full Analysis Set (FAS) will consist of all patients who provided informed consent and are 
treated with brolucizumab in this interventional study. All effectiveness and safety analyses will 
use the FAS population. 
7.6.3 
Patient demography and other baseline characteristics 
Demographics and other baseline characteristics will be collected at the first visit prior to the 
start of brolucizumab treatment. Descriptive statistics (as described under section 7.6.1 
“General statistical considerations” above) will be presented for continuous variables.  
The following variables will be summarized with descriptive statistics as outlined above: age, 
gender and baseline values of BCVA, baseline risk factors and ocular related history, and vital 
signs.  
Furthermore, the number (%) of patients will be summarized for prior nAMD treatments by 
WHO-DRL preferred term, for relevant medical histories by MedDRA primary system organ 
class and preferred term, and for other ocular conditions by type of condition. 

Novartis 
Confidential 
Page 22 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.6.4 
Treatments 
A data listing of the study drug (brolucizumab) received by the patient will be provided, and 
the proportion of participants receiving treatment will be summarized by visit. Exposure to 
study medication will be summarized by the duration (in days) from start to end of treatment 
within this interventional study. The number (%) of patients who discontinue prematurely prior 
to 56 weeks will be tabulated including the reasons for discontinuation. Furthermore, the 
number of injections will be presented for the total study period. 
In addition, the number and percentage of participants receiving rescue medications, 
concomitant medications, and significant non-drug therapy will be summarized by preferred 
term (coded by WHO ATC classification) and the same shall be listed. 
7.6.5 
Safety and Effectiveness analysis 
Primary Endpoint Analysis  
 Incidence and characteristics of treatment-emergent adverse events during the 56 
weeks of treatment with brolucizumab would be evaluated. 
Safety of brolucizumab treatment will be assessed by reported (ocular and systemic) adverse 
events (AEs). The incidence of AEs (new or worsened after the start of brolucizumab) will be 
summarized by MedDRA primary system organ class and preferred term. Similar summaries 
will be provided for fatal AEs and other serious AEs, AEs causing discontinuation of study 
drug, and AEs suspected to be related to the study medication (as assessed by the Investigator). 
Furthermore, AEs will be summarized by primary system organ class, preferred term and 
severity. Incidence rates will also be determined per treatment year, both for the first occurrence 
of an event and total events. An adverse event management protocol/mitigation plan would be 
provided to all the investigators to manage an event of intra-ocular inflammation.  
Secondary Endpoints Analysis  
The secondary endpoints will evaluate the effectiveness of brolucizumab in terms of change in 
the following parameters from Baseline to the end of week 56. BCVA at baseline, week 16 and 
56 including the change will be summarized with standard descriptive statistics.  
 Mean change in BCVA from baseline to week 16 and week 56 as measured by ETDRS 
letters.  
 Percentage (%) of patient eyes with gain in BCVA of 15/10/5 ETDRS letters or more at 
week 16 and week 56 
 Percentage (%) of patient eyes with loss in BCVA of 15/10/5 ETDRS letters or more at 
week 16 and week 56. 
 Number of anti-VEGF injections, non-injection visits and total number of visits  
 Percentage (%) of patient eyes with at least one duration of interval between injections 
≥ 8 weeks but <12 weeks. 
 Percentage (%) of patient eyes with at least one duration of interval between injections 
≥ 12 weeks. 

Novartis 
Confidential 
Page 23 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
 Percentage of patients with absence of intra-retinal fluid from baseline to week 16 and 
week 56. 
 Percentage of patients with absence of sub-retinal fluid from baseline to week 16 and 
week 56. 
 Estimated change in CST (in μm) from baseline to week 16 and week 56. 
7.7 
Quality control 
7.7.1 
Data quality management 
Novartis Data Management or/designated CRO will assure database quality processes are 
followed including review of the data entered into the eCRFs by investigational site staff for 
completeness and accuracy, and in accordance with the data validation plan. 
7.7.2 
Data recording and document retention 
In all scenarios, the Investigator must maintain source documents for each patient in the study, 
consisting of the case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, and the results of any other tests or assessments. All 
information entered in the eCRF must be traceable to these source documents in the patient’s 
file. 
The Investigator must give Novartis (or designee CRO) access to all relevant source documents 
to confirm their consistency with the eCRF entries. No information in source documents about 
the identity of the patients will be disclosed. 
The Investigator will retain a copy of all source documents and study records in accordance 
with the local regulations. The Investigator is recommended to contact Novartis before 
disposing off any study records. 
7.7.3 
Site monitoring 
The monitors appointed by the CRO/Novartis, or Novartis designee will perform all monitoring 
functions within this clinical study. Monitors will work in accordance with Standard Operating 
Procedures (SOPs) of Novartis or the CRO, as designated in the contract. Monitors will be 
responsible for establishing and maintaining regular contact between the Investigator and 
Novartis. Monitors will also control adherence to the protocol at the Investigator site. 
Monitors will evaluate the competence of each study center. Monitors will inform Novartis 
regarding problems relating to facilities, technical equipment, or medical staff. Monitors will 
ensure that written informed consent has been correctly obtained from all patients and during 
the study will ensure that data are recorded correctly and completely. 
Formal site monitoring will be performed as described in the Monitoring Plan for this study. 
Novartis Data Management/designated CRO will ensure compliance monitoring. 

Novartis 
Confidential 
Page 24 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
7.8 
Limitations of the research methods 
Limitations of Phase IV studies include the potential for observer bias due to lack of blinding 
and the absence of standardized data collection, and the potential for selection bias due to lack 
of randomization. However, this is a single-arm, open-label study and the patients would be 
eligible for this study only after the Investigator makes a decision to prescribe intravitreal 
brolucizumab. 
7.9 
Other aspects 
Every patient has the right to discontinue study participation at any time, and every patient may 
be discontinued from the study for any reason beneficial to his/her wellbeing. All data generated 
up to the time of discontinuation from the study will be analyzed and the reason(s) for 
discontinuation/withdrawal will be recorded. 
Patients must be discontinued from the study in the case of: 
 Withdrawal of informed consent to collect or use their data 
 Significant safety risk 
 The Investigator must record the discontinuation/withdrawal reason in the Case Record 
Form (CRF). Reasons that a patient discontinues treatment and participation from the 
study are considered to constitute one of the following: 
 Adverse event(s) 
 Unsatisfactory therapeutic effect 
 Subject's condition no longer requires study treatment 
 Subject withdrew consent 
 Lost to follow-up 
 Administrative problems 
 Death 
Patients who discontinue brolucizumab treatment should be asked to return for an early 
discontinuation assessment. 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 contacting the patients and asking 
them to return for a final assessment. Every effort should be made to obtain the reason for 
discontinuation. 
The Investigator should document in the source documents steps taken to contact the patient, 
e.g. dates of telephone calls, registered letters, etc. 
For the purpose of this study, the study drug brolucizumab will be provided free of costs for the 
patients in this study.  

Novartis 
Confidential 
Page 25 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
8 
Protection of human subjects 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/IEC/REB before the study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the Investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical Quality 
Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, 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. 
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 study 
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/REB, it cannot be implemented. 
8.1 
Regulatory and ethical compliance 
This clinical study is designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (New Drugs and Clinical Trial Rules, 2019 of the Drugs and Cosmetics Act, 
1945 (Govt. of India), US CFR 21, and with the ethical principles laid down in the Declaration 
of Helsinki. The study protocol and related information will be posted on India’s clinical trial 
registry – ctri.nic.in – before patient enrolment is started. 
Compliance with Novartis and regulatory standards provides assurance that the rights, safety, 
and well-being of patients participating in interventional studies are protected (consistent with 
the principles that have their origin in the Declaration of Helsinki) and that the study data are 
credible and responsibly reported. 
Written notification of approval for the study must also be obtained from an Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) prior to commencement of the study and 
will include the date of approval and signature of the chairman/member secretary. 
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of patients or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IEC/IRB annually, or more frequently if requested 
by the IEC/IRB. Upon completion of the study, the Investigator will provide the IEC/IRB with 
a brief report of the outcome of the study, if required. 
8.2 
Informed consent procedures 
The Investigator must keep the original informed consent form signed by the patient (a signed 
copy is given to the patient). 

Novartis 
Confidential 
Page 26 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative (LAR) of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
giving consent, he/she should personally sign and date the written informed consent. If the 
patient or LAR cannot read, then an impartial witness (independent of Novartis and 
Investigator) will witness and attest the entire consent process and will be required to sign the 
ICF. Informed consent must be obtained before any data are collected. The process of obtaining 
informed consent should be documented in the patient’s source documents. 
Novartis will provide Investigators or other involved medical professionals in a separate 
document a proposed informed consent form that complies with the Declaration of Helsinki 
principle and regulatory requirements and is considered appropriate for this study. 
8.3 
Responsibilities of the Investigator and IRB/IEC 
Before initiating a trial, the Investigator/Institution must obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, documented informed consent form, consent form 
updates, subject recruitment procedures (e.g. advertisements) and any other written information 
to be provided to patients/subjects. Prior to study start, the Investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Quality 
Assurance representatives, designated agents of Novartis, IRBs/IECs, and Regulatory 
Authorities as required. If an inspection of the clinical site is requested by a Regulatory 
Authority, the Investigator must inform Novartis immediately that this request has been made. 
9 
Safety Monitoring  
Any serious adverse events will be reported to the concerned Ethics Committee within 24 hours 
of the occurrence. All serious adverse events will also be reported to Novartis Patient Safety 
within 24 hours of the Investigator (or designee) being aware of the serious adverse event. 
Specific definitions of adverse events, and serious adverse events, are outlined below, along 
with reporting criteria required by Novartis.  
If the COVID-19 pandemic limits or prevents on-site study visits, phone calls or virtual contacts 
should be conducted for safety monitoring and discussion of the subject´s health status, until 
the subject can again visit the site. 
9.1 
Adverse events (AE) 
Information about all AEs, whether volunteered by the patient, discovered by Investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected and recorded on an Adverse Event Case Report Form and will be followed up as 
appropriate.  

Novartis 
Confidential 
Page 27 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
An AE is any undesirable sign, symptom or medical condition occurring after starting study 
treatment, even if the event is not considered to be treatment-related. Study treatment includes 
the study medication under evaluation, and any reference or placebo drug (or therapy) given 
during any phase of the trial. 
Medical conditions/diseases present before starting study treatment will only be considered 
adverse events if they worsen after starting study treatment (any procedures specified in the 
protocol). Adverse events (but not serious adverse events) occurring before starting study 
treatment but after signing the informed consent form will be recorded on the Medical 
History/Current Medical Conditions Case. 
For surveillance/monitoring of signs and symptoms related to Intra-ocular inflammation 
following initial injections of brolucizumab, the recommendations as mentioned below need to 
be followed by the study Investigator: 
 After Injecting brolucizumab, inform the patient about the symptoms of intra-ocular 
inflammation [eye pain, eye redness, blurred/decreased vision, dark, floating spots in 
the vision (floaters), light sensitivity, flashes, scotoma (blind spot in vision)]. 
 And inform the patient to report immediately if he/she sees/experiences any of the 
signs/symptoms as mentioned above. 
 When IOI, retinal vasculitis, and/or RAO is present or suspected during a visit, 
investigators must perform thorough ophthalmic examination, and will conduct OCT, 
fluorescein angiography and color fundus photography (preferably wide-field or with 
peripheral sweeps). 
 These additional assessments will be documented in the source and appropriate eCRF 
pages as applicable.  
 Follow-up the patient in the first week after injection to look for/assess symptoms 
(Phone call/Visit). 
 An adverse event management protocol/mitigation plan would be provided to all the 
investigators to manage an event of intra-ocular inflammation. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant or require therapy, and are recorded on 
the Adverse Events Case Report Form under the signs, symptoms or diagnosis associated with 
them. 
As far as possible, each adverse event will also be described by: 
1. the severity grade (mild, moderate, severe); 
2. its relationship to the drug(s) of interest (suspected/not suspected); 
3. its duration (start and end dates or if continuing at final exam); and 
4. whether it constitutes a serious adverse event (SAE); 

Novartis 
Confidential 
Page 28 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
9.2 
Serious Adverse Events (SAEs) 
Information about all serious adverse events will be collected and recorded on the Serious 
Adverse Event Report Form. To ensure patient safety each serious adverse event will also be 
reported to Novartis Patient Safety within 24 hours of the Investigator learning of its occurrence.  
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: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes); 
o 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 the drug of 
interest; or 
o 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 e.g. 
may require 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 
 Transmission of an infectious agent via medicinal product 
Any SAEs exempt from this reporting process must be clearly identified in the study protocol 
with a scientific/medical justification e.g. SAEs due to disease progression, SAEs due to a 
planned surgical procedure, etc. Any SAE study protocol exemptions MUST be agreed with the 
respective country health authority as part of the protocol approval process. This confirmation 
by the HA must be recorded and kept on file for the study concerned. 
Any SAE occurring after the patient has provided informed consent and until 4 weeks after the 
patient has stopped study participation will be reported. Serious adverse events occurring more 
than 4 weeks after study discontinuation will be reported to Novartis Patient Safety only if a 
relationship with the study therapy is suspected by the Investigator.  
As far as possible, each SAE will also be described by (but not limited to):  
 its duration (onset date = date of 1st signs or symptoms, and end dates); 
 the seriousness criteria and severity if applicable (mild, moderate, severe); 
 its relationship to the current investigational drug (suspected/not suspected as judged 
by the Investigator); 
 the action(s) taken and investigation results, if applicable; 
 concomitant medication details; and 
 outcome. 

Novartis 
Confidential 
Page 29 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
9.2.1 
Notification of serious adverse events to Novartis Pharmaceuticals  Patient 
Safety 
Each Serious Adverse Event (SAE) will be reported by the Investigator to Novartis Patient 
Safety within 24 hours of learning of its occurrence, even if it is not felt to be treatment-related. 
Follow-up information about a previously reported SAE will also be reported to Novartis 
Patient safety within 24 hours of receiving it. If the SAE has not been previously documented 
(new occurrence) and it is thought to be related to study treatment, Novartis Patient Safety 
Department may contact the Investigator to obtain further information.  
9.2.2 
Reporting procedures 
The Investigator will complete the SAE Report Form in English, assess the relationship to study 
treatment and send the completed and signed form by email within 24 hours to Novartis Patient 
Safety Novartis Patient Safety will acknowledge the receipt of the full SAE form (all pages) by 
email back. The original copy of the SAE Form, and the acknowledgement email will be kept 
with the case report forms at the study site. If the Investigator does not receive an 
acknowledgement email from Novartis Patient Safety within 24 hours or realize that the number 
of pages received by Novartis Patient Safety doesn’t match the number of pages emailed by the 
Investigator, the SAE form will be re-sent entirely until Novartis Patient Safety confirms the 
receipt of the full report.  
Follow-up information will be sent to the same person to whom the original SAE Form was 
sent, re-stating the date of the original report. A new SAE Form will be used (stating that this 
is a “follow-up”). The follow-up report should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or discontinued study 
participation. The SAE form and email acknowledgment will be retained by the study site. 
To ensure patient safety, each pregnancy in a patient will be reported to Novartis within 24 
hours of learning of its occurrence. Pregnancy will be recorded on a Clinical Trial Pregnancy 
Form and reported by the Investigator to the local Novartis Patient Safety Department. 
Pregnancy follow-up will be recorded on the same form and will include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy will be reported on the SAE Report Form.  
10 
Plans of disseminating and communicating study results 
Upon study completion and finalization of the study report, the results of this interventiona l 
study may be either submitted for publication and/or posted in a publicly accessible database of 
results. Publications will comply with internal Novartis standards and the International 
Committee of Medical Journal Editors (ICMJE) guidelines. 
 
 

Novartis 
Confidential 
Page 30 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
11 
References 
1. Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J; Vision Health 
Cost-Effectiveness Study Group. Forecasting age-related macular degeneration through the 
year 2050: the potential impact of new treatments. Arch Ophthalmol. 2009 Apr;127(4):533-
40. doi: 10.1001/archophthalmol.2009.58. PMID: 19365036. 
2. Kawasaki R, Yasuda M, Song SJ, Chen SJ, Jonas JB, Wang JJ, Mitchell P, Wong TY. The 
prevalence of age-related macular degeneration in Asians: a systematic review and meta-
analysis. Ophthalmology. 2010 May;117(5):921-7. doi: 10.1016/j.ophtha.2009.10.007. 
Epub 2010 Jan 27. PMID: 20110127. 
3. Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, Hofman A, Jensen S, Wang 
JJ, de Jong PT. Risk factors for age-related macular degeneration: Pooled findings from 
three continents. Ophthalmology. 
2001 Apr;108(4):697-704. 
doi: 
10.1016/s0161-
6420(00)00580-7. PMID: 11297486. 
4. Miller JW. Age-related macular degeneration revisited--piecing the puzzle: the LXIX 
Edward Jackson memorial lecture. Am J Ophthalmol. 2013 Jan;155(1):1-35.e13. doi: 
10.1016/j.ajo.2012.10.018. Erratum in: Am J Ophthalmol. 2018 Nov;195:249. PMID: 
23245386. 
5. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to 
neovascular 
maculopathy. 
Arch 
Ophthalmol. 
1984 
Nov;102(11):1640-2. 
doi: 
10.1001/archopht.1984.01040031330019. PMID: 6208888. 
6. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. 
Lancet. 2012 May 5;379(9827):1728-38. doi: 10.1016/S0140-6736(12)60282-7. PMID: 
22559899. 
7. Shah AR, Del Priore LV. Progressive visual loss in subfoveal exudation in age-related 
macular degeneration: a meta-analysis using Lineweaver-Burke plots. Am J Ophthalmol. 
2007 Jan;143(1):83-89. doi: 10.1016/j.ajo.2006.09.043. Epub 2006 Oct 20. PMID: 
17188044. 
8. Shah AR, Del Priore LV. Natural history of predominantly classic, minimally classic, and 
occult subgroups in exudative age-related macular degeneration. Ophthalmology. 2009 
Oct;116(10):1901-7. 
doi: 10.1016/j.ophtha.2009.03.055. 
Epub 2009 Jul 9. PMID: 
19592101. 
9. Blinder KJ, Bradley S, Bressler NM, Bressler SB, Donati G, Hao Y, Ma C, Menchini U, 
Miller J, Potter MJ, Pournaras C, Reaves A, Rosenfeld PJ, Strong HA, Stur M, Su XY, 
Virgili G; Treatment of Age-related Macular Degeneration with Photodynamic Therapy 
study group; Verteporfin in Photodynamic Therapy study group. Effect of lesion size, 
visual acuity, and lesion composition on visual acuity change with and without verteporfin 
therapy for choroidal neovascularization secondary to age-related macular degeneration: 
TAP and VIP report no. 1. Am J Ophthalmol. 
2003 Sep;136(3):407-18. 
doi: 
10.1016/s0002-9394(03)00223-x. PMID: 12967792. 
10. Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall 
RM, Witt KA, Ezrine S. Racial differences in the cause-specific prevalence of blindness in 

Novartis 
Confidential 
Page 31 
Interventional study protocol V 0.2 
 
Brolucizumab/CRTH258AIN01  
east 
Baltimore. 
N 
Engl 
J 
Med. 
1991 
Nov 
14;325(20):1412-7. 
doi: 
10.1056/NEJM199111143252004. PMID: 1922252. 
11. Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, 
Probst C, Sledge I. The natural history and prognosis of neovascular age-related macular 
degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 
2008 Jan;115(1):116-26. doi: 10.1016/j.ophtha.2007.03.008. Epub 2007 Aug 6. Erratum 
in: Ophthalmology. 2008 Sep;115(9):1524. Wong, Tien [corrected to Wong, Tien Y]. 
PMID: 17675159. 
12. Spilsbury K, Garrett KL, Shen WY, Constable IJ, Rakoczy PE. Overexpression of vascular 
endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the 
development of choroidal neovascularization. Am J Pathol. 2000 Jul;157(1):135-44. doi: 
10.1016/S0002-9440(10)64525-7. Erratum in: Am J Pathol 2000 Oct;157(4):1413. PMID: 
10880384; PMCID: PMC1850220. 
13. Campbell JP, Bressler SB, Bressler NM. Impact of availability of anti-vascular endothelial 
growth factor therapy on visual impairment and blindness due to neovascular age-related 
macular 
degeneration. 
Arch 
Ophthalmol. 
2012 
Jun;130(6):794-5. 
doi: 
10.1001/archophthalmol.2011.2480. PMID: 22801846. 
14. Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related macular 
degeneration in denmark: year 2000 to 2010. Am J Ophthalmol. 2012 Feb;153(2):209-
213.e2. doi: 10.1016/j.ajo.2011.10.016. PMID: 22264944. 
15. Nguyen QD, Das A, Do DV, Dugel PU, Gomes A, Holz FG, Koh A, Pan CK, Sepah YJ, 
Patel N, MacLeod H, Maurer P. Brolucizumab: Evolution through Preclinical and Clinical 
Studies and the Implications for the Management of Neovascular Age-Related Macular 
Degeneration. 
Ophthalmology. 
2020 
Jul;127(7):963-976. 
doi: 
10.1016/j.ophtha.2019.12.031. Epub 2020 Jan 17. PMID: 32107066. 
16. Brolucizumab Prescribing Information INDIA.  
17. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, 
Warburton J, Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. 
HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of 
Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 
Jan;127(1):72-84. 
doi: 10.1016/j.ophtha.2019.04.017. 
Epub 2019 Apr 12. PMID: 
30986442.