A Global, Phase III, Double Blind, Randomized Controlled Study to Compare the Efficacy, Safety & Immunogenicity of LUBT010 With Lucentis® in Patients With Neovascular Age Related Macular Degeneration
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Lupin Ltd.



 
Protocol Number: LRP/LUBT010/2016/008 
Version: 2.2; Dated 19 May 2022 
 
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STUDY SYNOPSIS 
Name of Sponsor/Company: 
Lupin  
Protocol No.: 
LRP/LUBT010/2016/008 
 
Name of Active Ingredient: 
Ranibizumab 
Title of Study: 
A Global, Phase III, Double Blind, Randomized Controlled Study to Compare the Efficacy, Safety & 
Immunogenicity of LUBT010 with Lucentis® in Patients with Neovascular Age-Related Macular Degeneration 
Study Sites: 
Approximately 75-100 sites across Europe, United States (US), and India having ophthalmologists who are 
experienced in diagnosing and treating neovascular age-related macular degeneration (AMD) 
Development Phase: Phase III 
Objectives: 
Primary Objective: 
To demonstrate the equivalence in efficacy of LUBT010 to Lucentis® in terms of visual acuity, in patients 
with Neovascular Age-Related Macular Degeneration. 
Secondary Objectives: 
• 
To assess the safety and tolerability of LUBT010 as compared to Lucentis®. 
• 
To assess the immunogenicity of LUBT010 as compared to Lucentis® 
 
Study Design: 
Global, Phase III, Double Blind, Randomized Controlled, two-arm, interventional study in patients with 
neovascular AMD. 
Methodology: 
Eligible patients with Neovascular AMD will be randomly assigned to receive either LUBT010 0.5 mg (0.05 
mL of 10 mg/mL ranibizumab) once monthly (intravitreal injection) or Lucentis® 0.5 mg (0.05 mL of 10 
mg/mL ranibizumab) once monthly (intravitreal injection) for 12 months.  
Patients will be randomized on Day 1. Only one eye per patient will receive the investigational product (IP).  
Patients will visit site for a safety visit after the first dose on any day from Day 2 to Day 9, followed by the 
next visit on Day 31 ± 2 days, and thereafter monthly for a total of 12 months (i.e. Day 61, Day 91, Day 121, 
Day 151, Day 181, Day 211, Day 241, Day 271, Day 301, Day 331, and Day 360), with an allowable visit 
window period of ± 2 days. A post injection visit/ telephonic safety assessment after every injection will be 
done as deemed necessary by Investigator. Efficacy, safety, and immunogenicity assessments will be done 
periodically. 
Day 360 ± 2 will be End of Study (EOS) visit.  
Number of Patients: 
Adequate number of patients will be screened to randomize approximately 600 patients to 2 treatment arms in 
1:1 ratio to have approximately 558 evaluable patients. 
Diagnosis and Main Criteria for Inclusion: 
Ambulatory male and female patients aged ≥50 years with active choroidal neovascularization (CNV) lesions 
involving the foveal center secondary to neovascular AMD, who are anti-VEGF naïve and having best 
corrected visual acuity (BCVA) in the study eye between 20/40 and 20/200 (Snellen equivalent), using Early 
Treatment Diabetic Retinopathy Study (ETDRS) chart testing.  
Investigational Product: 
The IPs will be supplied as:  
Test Product: LUBT010 supplied as single-use, 2-cc glass vial containing 2.3 mg of ranibizumab in 0.23 
mL solution designed to deliver 0.05 mL of 10 mg/mL ranibizumab, by intravitreal injection. 

 
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Name of Sponsor/Company: 
Lupin  
Protocol No.: 
LRP/LUBT010/2016/008 
 
Name of Active Ingredient: 
Ranibizumab 
Reference Medicinal Product: EU-approved Lucentis® supplied as single-use, 2-cc glass vial containing 
2.3 mg of ranibizumab in 0.23 mL solution designed to deliver 0.05 mL of 10 mg/mL ranibizumab, by 
intravitreal injection. 
Dose and Administration: 
Ranibizumab 0.5 mg (Lucentis® or LUBT010) will be administered once every month as intravitreal injection 
for 12 months. Total 12 injections would be given to each patient. 
Study Duration: Approximately 13 months 
• 
Screening Period: Maximum 28 days 
• 
Treatment and Subsequent Assessments: 12 months 
Study Endpoints: 
Primary Endpoint: 
Mean change in BCVA from baseline in the study eye at the end of 12 months, assessed with the ETDRS chart. 
Secondary Endpoints: 
Efficacy:  
• 
Mean change in BCVA from baseline in the study eye at the end of 3 months assessed with the 
ETDRS chart. 
• 
Mean change in BCVA from baseline in the study eye at the end of 6 and 9 months, assessed with 
the ETDRS chart. 
Safety: 
• 
Adverse Events (AE) assessment, ocular and non-ocular 
• 
Ophthalmic examination 
• 
Physical and systemic examination  
• 
Vital signs  
• 
Electrocardiogram (ECG) 
• 
Laboratory parameters: Blood (hematology and biochemistry) and urinalysis 
Immunogenicity: 
Proportion of patients with anti-drug antibodies at the end of 1, 3, 6, 9, and 12 months. 
 
Exploratory Endpoint: 
• 
Mean change from baseline in National Eye Institute Visual Functioning Questionnaire – 25 (NEI-
VFQ-25) Version 2000 (interviewer administered) scores at 3, 6, and 12 months. 
 
Statistical Methods: 
The primary endpoint of change in BCVA from baseline in the study eye at the end of 12 months will be 
analyzed using ANCOVA model with treatment as fixed-effect, and baseline BCVA as covariate. The 
equivalence of efficacy will be assessed based on 90%# (two-sided) confidence interval for the difference in 
mean change in BCVA from baseline in the study eye at end of 12 months, with an equivalence margin of 4 
letters. (# As generally required by US Food and Drug Administration [FDA]) 
Similarly, the equivalence of efficacy will be assessed based on 95%## confidence interval of the difference in 
mean change in BCVA from baseline in the study eye at the end of 12 months, with an equivalence margin of 
4 letters. (## As generally required by the European Medicines Agency [EMA].) 
 
For continuous data, summary statistics will include the number, arithmetic mean, standard deviation (SD), 
median, minimum, and maximum. For categorical data, frequency and percentage will be presented. 
The safety data and immunogenicity data will be summarized and listed. 
 

 
 
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Explanation of symbols used: 
@ 
A post injection visit/ telephonic safety assessment after every injection will be done as deemed necessary by Investigator. 
# 
In the situation where the day of first dosing is different from day of randomization, all the visit days should be calculated from Day 1 (day of first dosing) rather than day of 
randomization. 
1  
Confirmation of eligibility (based on screening results and Investigations done on Day 1) 
2 
Includes body temperature, pulse rate, blood pressure, and respiratory rate. Should be done pre & post treatment on injection days. 
3 
Hematology: Complete blood count (CBC) [haemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), platelets, and differential blood cell counts (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils)] 
ECG7 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
IP administration 
(study eye only)8 
 
X8 
 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
 
Adverse event 
assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/ 
treatment10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Refraction 
assessment11 
X12 
X13 
 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X 
BCVA with ETDRS 
starting @ 4 meters11 
X12 
X13 
 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X 
Ophthalmoscopic 
examination (Indirect 
dilated)  
X 
X14 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X 
Slit lamp 
examination 
X 
X13 
X 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X 
Intraocular pressure 
measurement15 
X 
X16 
X 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X16 
X 
Fluorescein 
angiography17,18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optical coherence 
tomography (OCT)17 
X19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
Immunogenicity13, 20 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
NEI-VFQ-25 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 

 
 
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Blood chemistry: Bilirubin (total, direct, indirect), alkaline phosphatase, ALT, AST, BUN, total protein, albumin, globulin, uric acid, urea, creatinine, random glucose 
Urinalysis: 
Appearance, 
color, 
specific 
gravity, 
pH, 
protein, 
glucose, 
ketones, 
urobilinogen, 
occult 
blood 
(and 
microscopic 
examination).  
(Repeat test can be conducted, if required. Additional investigations may be performed at the discretion of investigator to ensure subject safety.) 
4 
Including Serology: HIV, HBV (HbsAg), HCV, and Syphilis (RPR). Follicle stimulating hormone (FSH) to be done in all females at screening. 
5 
To be done in females of childbearing potential (females who are not surgically sterile or menopausal).  
6 
Serum/ Urine pregnancy test can be repeated anytime in local/ central laboratory when pregnancy is suspected in any female patient. Urine pregnancy test to be performed by the 
female patients themselves and the results reported to site during the visit.  
7 
Electrocardiogram (ECG) assessment can be done during any of the visits if the patient complains of any symptoms pointing towards a cardiovascular condition. 
8  
Drug to be administered as per recommendations (e.g. prophylactic antimicrobial therapy, aseptic precautions, monitoring for AEs). Patient will be observed for at least 
60 min (± 30 min) post injection. Interval between 2 intravitreal injections of ranibizumab should not be less than 28 days  
9 
Elicit reports of any decrease in vision, eye pain, unusual redness or any other new ocular symptoms in the study eye, or any other AEs. On drug administration visits, AE assessment 
will be performed pre and postdose. 
10  
Includes medication for previous treatment for AMD or any other ocular condition within 3 months prior to screening and Protocol specified procedural medications (e.g. dilating 
drops, fluorescein dyes etc.) and pre & post medications used by the patients or any other systemic treatments 
11 
To be performed prior to dilating eyes by technicians trained and qualified to measure BCVA. BCVA assessment should begin at a starting distance of 4 meters. 
12  
Refraction and Visual acuity testing should be done prior to other ophthalmic investigations during screening. Only when the patient is eligible based on BCVA, the remaining 
investigations should be done. The order in which various other procedures are performed may vary from clinic to clinic, provided the procedures are completed within screening 
period. 
13  
To be performed pre-treatment 
14 
Predose (both eyes) & Post dose (study eye only) 
15 
Measurement method used for a patient to be preferably consistent throughout the study 
16 
Obtained pre-treatment for both eyes and 60 min (± 30 min) post injection for study eye only 
17 
Fundus photographs/ soft copy to be retained as source document 
18 
Known history of sensitivity to fluorescein dye to be checked before Fluorescein angiography 
19 
To be done in both eyes at screening and in study eye after every injection within a month unless not considered necessary by PI as decided by clinical examination.  
20 
Blood samples for immunogenicity to be collected, before dosing study drug (predose) at Day 1, Day 31, Day 91, Day 181, Day 271, and at EOS visit (Day 360). 
21 
In case of early discontinuations/ premature termination of the study all EOS investigations should be done on the day of termination as far as possible. 
 
 

 
 
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1 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................... 2 
STUDY SYNOPSIS ........................................................................................................... 3 
1 
TABLE OF CONTENTS .................................................................................... 10 
1.1 
List of Tables .......................................................................................... 13 
1.2 
List of Figures......................................................................................... 13 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 13 
3 
INTRODUCTION ............................................................................................... 15 
3.1 
Background............................................................................................. 15 
3.2 
Scientific Findings , ................................................................................ 16 
3.3 
Rationale ................................................................................................. 17 
3.4 
Risk-Benefit Assessment ........................................................................ 19 
3.4.1 
Risk Assessment related to COVID-19 Pandemic ............................. 19 
4 
STUDY OBJECTIVES ....................................................................................... 20 
4.1 
Primary Objective ................................................................................... 20 
4.2 
Secondary Objectives ............................................................................. 20 
5 
STUDY ENDPOINTS ......................................................................................... 21 
5.1 
Primary Efficacy Endpoint ..................................................................... 21 
5.2 
Secondary Endpoints .............................................................................. 21 
5.2.1 
Efficacy .............................................................................................. 21 
5.2.2 
Safety ................................................................................................. 21 
5.2.3 
Immunogenicity ................................................................................. 21 
5.3 
Exploratory Endpoint ............................................................................. 21 
6 
INVESTIGATIONAL PLAN .............................................................................. 22 
6.1 
Overall Study Design and Plan............................................................... 22 
6.2 
Discussion of Study Design.................................................................... 23 
6.2.1 
Choice of Study Population ............................................................... 23 
6.2.2 
Appropriateness of Measurements ..................................................... 23 
6.2.3 
Control Group .................................................................................... 24 
6.2.4 
Duration of Study .............................................................................. 24 
6.3 
Schedule of Assessments ........................................................................ 24 
6.3.1 
Detailed Study Assessments .............................................................. 24 
6.4 
Selection of Study Population ................................................................ 28 
6.4.1 
Inclusion Criteria ............................................................................... 28 
6.4.2 
Exclusion Criteria .............................................................................. 29 
6.4.3 
Withdrawal and Discontinuation of Patients ..................................... 30 
6.4.4 
Rescreening of Patients ...................................................................... 32 

 
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6.4.5 
Other Patient Restrictions .................................................................. 32 
6.4.6 
Early Termination of Study/ Site ....................................................... 32 
7 
TREATMENT OF PATIENTS AND INVESTIGATIONAL PRODUCT 
MANAGEMENT ................................................................................................ 33 
7.1 
Treatment of Patients .............................................................................. 33 
7.1.1 
Dosages & Treatment Regimen ......................................................... 33 
7.1.2 
Precautions while Administering Investigational Product ................. 33 
7.1.3 
Randomization of Study Treatments ................................................. 33 
7.1.4 
Blinding of Study Treatment ............................................................. 34 
7.1.5 
Patient Compliance ............................................................................ 34 
7.1.6 
Concomitant Therapy ........................................................................ 34 
7.2 
IP MANAGEMENT ............................................................................... 35 
7.2.1 
IP Dosage Form and Strength ............................................................ 35 
7.2.2 
IP Packaging and Labelling ............................................................... 35 
7.2.3 
Storage ............................................................................................... 35 
7.3 
IP Supply, Handling and Accountability ................................................ 36 
8 
ASSESSMENT OF EFFICACY ......................................................................... 37 
8.1 
Efficacy Endpoints ................................................................................. 37 
8.2 
Efficacy Variables .................................................................................. 37 
9 
ASSESSMENT OF SAFETY.............................................................................. 38 
9.1 
Adverse Events ....................................................................................... 38 
9.1.1 
Definitions ......................................................................................... 38 
9.1.2 
Recording and Collection of Adverse Events .................................... 39 
9.1.3 
Evaluation of Adverse Events ............................................................ 40 
9.1.4 
Ocular AEs ......................................................................................... 42 
9.1.5 
Non-Ocular AEs due to VEGF inhibition .......................................... 43 
9.2 
Ophthalmic Examination ........................................................................ 43 
9.3 
Physical and Systemic Examination ....................................................... 43 
9.4 
Vital Signs .............................................................................................. 43 
9.5 
Electrocardiogram Assessments ............................................................. 43 
9.6 
Clinical Laboratory Examinations .......................................................... 44 
9.6.1 
Central Laboratory Samples .............................................................. 44 
9.7 
Pregnancy ............................................................................................... 45 
10 
ASSESSMENT OF IMMUNOGENICITY ......................................................... 46 
10.1 
Anti-Drug Antibodies ............................................................................. 46 
10.1.1 
Collection, Handling, and Analysis of Immunogenicity Samples ..... 46 
11 
STATISTICAL EVALUATION ......................................................................... 47 
11.1 
Sample Size and Power .......................................................................... 47 

 
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11.2 
Statistical Methods ................................................................................. 47 
11.2.1 
Significance Level and Confidence Interval ...................................... 48 
11.2.2 
Criteria for Equivalence ..................................................................... 48 
11.3 
Handling of Missing Data ...................................................................... 48 
11.4 
Patient Disposition.................................................................................. 48 
11.5 
Baseline and Demographic Characteristics ............................................ 49 
11.6 
Analysis Sets .......................................................................................... 49 
11.6.1 
Full Analysis Set (FAS) ..................................................................... 49 
11.6.2 
Per Protocol Analysis Set (PPS) ........................................................ 49 
11.6.3 
Safety Analysis Set (SAF) ................................................................. 49 
11.6.4 
Immunogenicity Analysis Set (IGS) .................................................. 49 
11.7 
Efficacy Analysis.................................................................................... 49 
11.7.1 
Primary Efficacy Endpoint ................................................................ 49 
11.7.2 
Secondary Efficacy Endpoints ........................................................... 50 
11.7.3 
Exploratory Endpoint ......................................................................... 50 
11.8 
Safety Analysis ....................................................................................... 51 
11.8.1 
Parameters for Assessment of Safety ................................................. 51 
12 
DATA MANAGEMENT .................................................................................... 53 
12.1 
Data Handling ......................................................................................... 53 
13 
CLINICAL STUDY MANAGEMENT .............................................................. 54 
13.1 
Conduct of the Study .............................................................................. 54 
13.2 
Direct Access to Source Data ................................................................. 54 
13.3 
Amendments to the Protocol .................................................................. 54 
13.4 
Guidance and Supervision of Sub-Investigators .................................... 54 
13.5 
Archiving Study Records ....................................................................... 54 
14 
QUALITY ASSURANCE AND QUALITY CONTROL .................................. 56 
14.1 
Monitoring .............................................................................................. 56 
14.2 
Agreement and Compliance with the Protocol ....................................... 56 
14.3 
Audits and Inspections ........................................................................... 56 
15 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .............................. 57 
15.1 
IEC/IRB Approval .................................................................................. 57 
15.2 
Written Informed Consent ...................................................................... 57 
15.3 
Confidentiality ........................................................................................ 57 
15.4 
Liability and Insurance ........................................................................... 57 
15.5 
Publication Policy ................................................................................... 58 
16 
APPENDICES ..................................................................................................... 59 
16.1 
Appendix A: Preparation for Administration ......................................... 59 
16.2 
Appendix B: Study Management Details ............................................... 59 
16.3 
Appendix C: Investigator’s Signature Page ........................................... 59 

 
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16.4 
Appendix D: Visual Functioning Questionnaire .................................... 59 
17 
REFERENCE LIST ............................................................................................. 60 
 
1.1 
List of Tables 
Table 1: Schedule of Assessment ....................................................................................... 5 
Table 2: Doses and Treatment Regimen ........................................................................... 33 
Table 3: IP Details  ......................................................................................................... 35 
Table 4: Clinical Laboratory ............................................................................................. 44 
 
1.2 
List of Figures 
Figure 1: Study Flow Chart................................................................................................. 8 
 

 
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3 
INTRODUCTION 
3.1 
Background 
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among 
people who are 50 years of age or older in the developed world. AMD has become an important 
and increasing cause of retinal blindness in developing countries, along with Diabetic 
Retinopathy (DR)in adults1.Globally, AMD ranks third as a cause of blindness after cataract 
and glaucoma. The main risk factor is ageing. Other risk factors may include the use of tobacco, 
genetic tendencies, the degree of pigmentation (with light colored eyes being at higher risk), 
arterial hypertension, the ultraviolet rays, and consumption of a non-balanced diet.2There is 
some evidence that links both cardiovascular and inflammatory biomarkers to AMD. The 
genetic etiology of AMD continues to be an area of research and investigation.3 
 
Age-related macular degeneration (AMD) is a chronic degenerative disorder of the retina that 
causes progressive loss of central vision and is a leading cause of blindness in older adults.4 
Age-related macular degeneration is classified into two different types: the non-exudative (or 
dry) form and the exudative (wet or neovascular) form. The dry form is the most prevalent, 
accounting for 90% of the cases. The onset and progression of either type do not follow any 
particular pattern. It is not uncommon that the dry form develops into the wet form of AMD in 
which new choroidal vessels are developed. The latter form causes the worst incapacity and 
accounts for approximately 90% of severely impaired vision in AMD. In this process, the 
oxygen supply to the macula is disrupted and as a response to ischemia, new, immature, leaky 
blood vessels are formed. These may grow through breaks of the membrane behind the retina, 
towards the macula, often lifting the retina and causing hemorrhage in the sub-retinal space. 
Eventually, the lesions may turn into scars resulting in destruction of the macula and loss of 
central vision. The angiographic classification of AMD lesions includes determination of the 
lesion size, the proportion of the entire AMD lesion that consists of ‘classic’, minimally classic, 
and ‘occult’ choroidal neovascularization (CNV).5 
 
The World Health Organization (WHO) estimates that neovascular AMD affects 3 million 
people globally, accounting for 8.7% of all blindness and 50% of blindness in industrialized 
countries.6 The global prevalence of AMD is expected to increase to 288 million by the year 
2040.7.If left untreated, the visual prognosis for eyes with neovascular AMD is poor. Also, 
AMD adversely affects quality of life and activities of daily living, causing many affected 
individuals to lose their independence in their retirement years.3  
Although neovascular AMD (nAMD) accounts for only 10%–20% of the overall cases of 
AMD, it accounts for 80% to 90% of AMD-associated vision loss. For neovascular AMD, the 
visual loss is progressive. Patients with unilateral nAMD have a 4% to 12% risk of CNV 
developing in the second eye 1 year after diagnosis, and between 20% and 42% of such patients 
harbor the risk of CNV developing 2 to 3 years after diagnosis. Although, no complete cure 
exists, the available treatment options maintain or improve vision, or both.8 
 
Vascular endothelial growth factor (VEGF) has been implicated as playing an important role 
in the pathogenesis of neovascular AMD. Vascular endothelial growth factor A (VEGF-A), a 
diffusible cytokine that promotes angiogenesis and vascular permeability, has been implicated 
as an important factor for promoting neovascularization.9 
 

 
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Introduction of VEGF anti-angiogenesis therapy produced a true paradigm shift in the 
treatment of neovascular (wet) AMD. Anti-angiogenic therapy, aimed at halting abnormal 
blood vessel growth, became recognized as an entirely new class of disease treatment and has 
become the first line of treatment in neovascular-AMD.6 However, pegaptanib, the first 
anti-VEGF agent although reduced the rate of vision loss, did not show significant 
improvement in vision. Off-label use of bevacizumab for neovascular AMD raised safety 
concerns due to the potential increased incidence of arterial thromboembolic events. Besides 
bevacizumab being a full-length antibody was thought to be difficult to penetrate all the layers 
of retina & choroid. Therefore, ranibizumab was engineered as a recombinant humanized 
immunoglobulin G1 kappa isotype monoclonal antibody fragment with a small molecular size 
and lack of Fc portion of the antibody which eliminates the possibility of complement-
mediated or cell-dependent cytotoxicity triggered by interaction of the Fc receptors with 
inflammatory cells. Since the introduction of ranibizumab, the monoclonal antibody fragment 
against all isoforms of VEGF-A, anti-VEGF therapy revolutionized the treatment of 
neovascular AMD and other VEGF related retinal diseases. Ranibizumab not only halted the 
vision loss but also increased the visual acuity with lesser of systemic VEGF related adverse 
events (AEs). 
 
Lupin has developed an investigational biosimilar of ranibizumab (referred as LUBT010 in 
this clinical study protocol) and intends to conduct a clinical study in order to market the 
product in global markets (United States [US], European Union [EU], and India). As per 
regulatory requirements, quality parameters have been established and a Pre-clinical Toxicity 
(PCT) study has shown that LUBT010 is safe in doses tested (up to 3 times human dose) and 
well tolerated when given as intravitreal injection. The planned Phase III study will provide 
data on similarity of Lucentis® and LUBT010 in terms of efficacy, safety and immunogenicity. 
3.2 
Scientific Findings 10,11 
Innovator’s ranibizumab (Lucentis®)/ the Reference Medicinal Product (RMP) was approved 
in 2006.  
Lucentis® is indicated in adults for the treatment of Neovascular (wet) Age-related Macular 
Degeneration (AMD), Macular edema following Retinal Vein Occlusion (RVO), Diabetic 
Macular Edema (DME) and Diabetic Retinopathy (DR) and Myopic Choroidal 
Neovascularization (mCNV). Lucentis® is also indicated in preterm infants for: Treatment of 
retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or 
APROP (aggressive posterior ROP) disease.  
Ranibizumab is administered 0.5 mg (0.05 mL) by intravitreal injection once a month 
(approximately 28 days).  
 
Based on the population pharmacokinetic analysis of patients with neovascular AMD, 
maximum serum concentrations reached at approximately 0.512 to 1 day after monthly 
intravitreal administration of ranibizumab 0.5 mg/eye. The apparent half-life of ranibizumab 
in serum after intravitreal administration was equivalent to the vitreous elimination half-life 
(approximately 9 days). Steady-state minimum concentration was 0.22 ng/mL with a monthly 
dosing regimen. Systemic exposure range was 1.7 (±1.1) ng/mL, which was below the 
concentration necessary to inhibit the biological activity of VEGF-A by 50% (11 to 27 ng/mL).  
Due to the negligible and variable systemic exposure after intravitreal administration, systemic 
pharmacokinetics (PK) is not considered surrogate of efficacy which is measured in terms of 

 
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visual acuity. In humans, although the serum ranibizumab concentrations were several-fold 
lower than vitreal concentrations, some systemic side effects related to anti-VEGF have been 
observed. However, data available from the 2-year MARINA study has demonstrated that 
those events that were considered of specific concern (ie, arterial thromboembolic events) were 
more balanced between sham and active arms. 
 
No special dosage modification is required for any of the populations that have been studied 
(e.g., gender, elderly or renal impairment status). The systemic exposures are very low after 
ocular administration, but due to its mechanism of action, ranibizumab is regarded as 
potentially teratogenic and embryo-/fetotoxic and must not be used in pregnant and lactating 
women unless absolutely needed due to the potential risk to the fetus. Women of childbearing 
potential should use effective contraception during treatment. Safety has not been established 
in nursing women or pediatric patients; breast-feeding is not recommended during the use of 
ranibizumab. 
 
The most frequently reported ocular adverse reactions following injection of Lucentis® are eye 
pain, ocular hyperemia, increased intraocular pressure, vitritis, vitreous detachment, retinal 
hemorrhage, visual disturbance, vitreous floaters, conjunctival hemorrhage, eye irritation, 
foreign body sensation in eyes, increased lacrimation, blepharitis, dry eye and eye pruritus. The 
most frequently reported non-ocular adverse reactions are headache, nasopharyngitis and 
arthralgia.  
Less frequently reported, but more serious, adverse reactions include endophthalmitis, 
blindness, retinal detachment, retinal tear and iatrogenic traumatic cataract. 
 
The investigational biosimilar of Lupin is also supplied as a single-use, 2-cc glass vial 
containing 2.3 mg of ranibizumab in 0.23 mL designed to deliver 0.05 mL of 10 mg/mL 
ranibizumab, by intravitreal injection. The PCT study that has been conducted with LUBT010 
includes the repeated dose (4-week) intravitreal toxicity study in rabbit with 14-day recovery 
period. 
 
Pre-clinical program of Lupin’s biosimilar ranibizumab revealed that it is safe and well 
tolerated when given intravitreally. Moreover, it is also well tolerated at the site of injections. 
Lupin has demonstrated analytical, functional and in vivo nonclinical similarity to Lucentis®. 
Therefore, Lupin intends to take this product forward in the clinical development. 
3.3 
Rationale 
Ranibizumab is a valuable treatment option for patients with neovascular (wet) AMD. The 
safety and tolerability of Lucentis® has been studied in various Phase 1 to 4 clinical studies. 
The results have demonstrated well accepted efficacy and safety profile. The reference 
medicinal product for this study – Lucentis® is approved and available in the market globally 
since 2006. Therefore, the risks are well known, and the benefits outweigh the risks for the 
treatment of neovascular AMD.  
 
Ranibizumab interferes with a small protein known as VEGF that stimulates the very 
angiogenesis that lies at the heart of neovascular AMD. Based on sound pathological 
mechanism of action, ranibizumab addresses the unmet need in the treatment of neovascular 
(wet) AMD. However, the high costs of treatment have been a major issue of concern making 

 
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it practically unaffordable to the common people. This has made off-label anti-VEGF agent 
bevacizumab the preferred choice against the regulatory framework.9 
Therefore, development of biosimilar of ranibizumab has become imperative and the need for 
encouragement of companies for developing biosimilars has gained importance so that the right 
to treatment can be equally bestowed to everyone in need. Introduction of biosimilar of 
ranibizumab would offer a cost-effective option for treatment of patients with neovascular 
AMD. 
 
LUBT010 has been developed as an investigational biosimilar of Lucentis® and has been found 
to be safe and well tolerated in pre-clinical program so far (similarity has been demonstrated 
through quality/ analytical and PCT studies). This Phase III clinical study in patients with 
neovascular AMD, is a part of biosimilar development pathway and in line with regulatory 
requirements, to demonstrate the biosimilarity between Lucentis® and LUBT010. The 
indication selected is one of the major indications studied by the innovator. The biosimilar 
development requires a comparative similarity with reference biologic at all steps of 
development, thus the RMP ‘Lucentis®’ is the active control arm. 
 
This study has mean change in Best Corrected Visual Acuity (BCVA) from baseline as the 
primary endpoint. This is a globally accepted primary end point. The methodology used to 
measure visual acuity is by using Early Treatment Diabetic Retinopathy Study (ETDRS) chart 
which has been endorsed by the Food and Drug Administration (FDA).13 Assessment of 
immunogenicity is of critical importance to characterize potential differences between the 
biosimilar candidate and the reference medicinal product in terms of the incidence and severity 
of human immune responses and is considered a key component of a biosimilar’s clinical 
development program. Since both pre-treatment and post treatment incidences of antibodies 
have been reported with Lucentis®, comparative immunogenicity assessment has also been 
included in this trial. 
 
This study includes monthly injections of ranibizumab (LUBT010 or Lucentis®) for a treatment 
duration of 12 months. The US prescribing information for Lucentis® recommends monthly 
injections for optimal visual acuity outcomes. Studies have also suggested higher efficacy with 
monthly regimen as compared to PRN regimen with statistically significant difference of 
2.4 letters found in favor of monthly dosing compared with PRN treatment.9 Neovascular 
AMD, being a chronic progressive disease, patients are required to receive therapy for long 
duration. In addition, the landmark trials for ranibizumab (ANCHOR14 MARINA15 and 
HARBOR16) have satisfactorily evaluated the primary endpoints with 12 monthly injections. 
As per the MARINA trial results, more than 90% of patients in each treatment group remained 
in the study at 12 months, thus meeting the endpoints satisfactorily. Therefore, a study duration 
of 12 months with monthly injection intervals is considered appropriate for assessment of 
efficacy, safety, and immunogenicity in this study. 
 
 

 
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3.4 
Risk-Benefit Assessment 
Since LUBT010 has been developed as an investigational biosimilar to Lucentis®, its risk/ 
benefit profile is considered to be similar to that of Lucentis®. The safety and tolerability of 
Lucentis® have been studied in various Phase 1 to 4 clinical studies. The results have 
demonstrated well accepted efficacy and safety profile. The impressive results with 
ranibizumab are far superior to those seen with PDT or pegaptanib. Therefore, monotherapy 
ranibizumab has become the standard of care for patients with subfoveal CNV due to AMD 
regardless of type and size of lesion.16 The reference medicinal product ranibizumab 
(Lucentis®) is approved and available in the market globally since 2006; therefore benefits are 
well proven and the risks are known for the treatment of AMD. 
 
The risks associated with the use of RMP are summarized in the Summary of Product 
Characteristics10 and Prescribing Information11 of Lucentis®. It is advised that the injection be 
administered only by qualified ophthalmologists experienced in intravitreal injections with 
adequate aseptic precautions, prophylactic antimicrobial therapy, and monitoring for AEs. If 
these precautions are taken care of, Lucentis® is a valuable therapy for the treatment of AMD. 
 
In the pre-clinical development program, LUBT010 was found to be comparable to the 
Lucentis® and has shown that the PCT profile is acceptable and did not reveal any significant 
toxicity at doses which were up to 3 times of human doses. 
 
Since LUBT010 is an investigational biosimilar of Lucentis®, it is anticipated that the patients 
randomized to the LUBT010 arm will have a similar potential for benefit from treatment as 
those randomized to the Lucentis® arm.  
3.4.1 
Risk Assessment related to COVID-19 Pandemic 
As per EMA guidance on the management of clinical trials during the COVID-19 (coronavirus) 
pandemic, ongoing risk assessments of the impact of the COVID-19 pandemic on the study 
will be performed. A risk mitigation/contingency plan is prepared for this purpose and takes 
into account current knowledge about COVID and mitigation of potential uncertainties. 
 

 
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4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To demonstrate the equivalence in efficacy of LUBT010 to Lucentis® in terms of visual acuity, 
in patients with neovascular Age-Related Macular Degeneration. 
 
4.2 
Secondary Objectives 
• To assess the safety and tolerability of LUBT010 as compared to Lucentis®. 
• To assess the immunogenicity of LUBT010 as compared to Lucentis®. 
 

 
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5 
STUDY ENDPOINTS 
5.1 
Primary Efficacy Endpoint 
Mean change in BCVA from baseline in the study eye at the end of 12 months, assessed with 
the ETDRS chart. 
 
5.2 
Secondary Endpoints 
5.2.1 
Efficacy 
• Mean change in BCVA from baseline in the study eye at the end of 3 months, assessed 
with the ETDRS chart. 
• Mean change in BCVA from baseline in the study eye at the end of 6 and 9 months, 
assessed with the ETDRS chart. 
 
5.2.2 
Safety 
• Adverse Events (AE) assessment, ocular and non-ocular 
• Ophthalmic examination 
• Physical and systemic examination 
• Vital signs  
• Electrocardiogram (ECG) 
• Laboratory parameters - Blood (hematology and biochemistry) and urinalysis 
5.2.3 
Immunogenicity 
Proportion of patients with anti-drug antibodies at the end of 1, 3, 6, 9, and 12 months. 
5.3 
Exploratory Endpoint 
• Mean change from baseline in National Eye Institute Visual Functioning Questionnaire 
– 25 (NEI-VFQ-25) Version 2000 (interviewer administered) scores at 3, 6, and 
12 months. 

 
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6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
This is a global, Phase III, double blind, randomized, controlled clinical study. The objective 
of the study is to compare the efficacy, safety and immunogenicity of LUBT010 to that of 
Lucentis® in patients with neovascular AMD. 
 
Approximately 75 –100 sites across Europe, US, and India, having ophthalmologists who are 
experienced in diagnosing and treating neovascular AMD, and where adequate facilities for 
conduct of trial are available will be selected for the study. Study will be initiated only after 
receipt of regulatory and EC approval. Screening investigations on patient will be done only 
after signing of written informed consent. Adequate number of patients will be screened to 
randomize approximately 600 patients to have 558 evaluable patients in the study. (Note: 
Every attempt will be made to ensure at least 25% of patients enrolled are with light colored 
irises). 
 
Patients will be randomized on Day 1. Total 12 injections (Lucentis® or LUBT010 0.5 mg 
intravitreal injection, once monthly) would be given to each patient during the study. The 
duration of the treatment and assessments will be 12 months during which the efficacy, safety 
and immunogenicity assessments will be done. The total study duration for each patient would 
be around 13 months. It would include up to 28 days of screening period and 12 months of 
treatment and assessment period. 
 
The trial consists of following parts: 
 Screening Period (maximum 28 days) 
 Treatment and Assessment Period (12 months) 
o Day 1 (Randomization and first dose of ranibizumab) 
o Safety Visit: Day 2 to 9 (on any day from Day 2 to Day 9) 
o Treatment visits (± 2 days): Day 31 (second dose), and thereafter monthly for a 
total of 12 months (i.e. Day 61, Day 91, Day 121, Day 151, Day 181, Day 211, 
Day 241, Day 271, Day 301, and Day 331) followed by post-injection 
visit/Telephonic Follow-Up, as deemed necessary by Investigator. 
o Day 360 (± 2 days) - End of Study (EOS) 
 
After signing the informed consent form, the patients will undergo screening assessments to 
confirm eligibility. These include demographics, medical and surgical history, (including 
ophthalmic history), weight, ECG, vital signs, physical, systemic and ophthalmic examination, 
and laboratory assessments (blood and urine) as given in Table 1.  
Screening period will be of maximum 28 days. The eligible patients will then be randomized 
on Day 1 in 1:1 ratio, to receive either LUBT010 or Lucentis® as an intravitreal injection. The 
patients will visit the clinical facility for all 12 injections which will be administered once a 
month. 
In a situation where the day of first dosing is different from day of randomization, all the visit 
days should be calculated from Day 1 (day of first dosing) rather than day of randomization. 
 

 
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Assessment of efficacy, safety, and immunogenicity will be done periodically during the study 
as given in the schedule of assessment table (Table 1). 
Safety includes AE assessment (ocular and non-ocular), ophthalmic examination, and changes 
from baseline in vital signs, physical and systemic examination, ECG, and laboratory 
parameters. 
6.2 
Discussion of Study Design 
This is a global, phase III, double blind, randomized controlled interventional study to be 
carried out in patients with neovascular AMD. The present study is designed in conformance 
with guidelines on biosimilar development which requires demonstration of comparable 
efficacy and safety between the investigational biologic LUBT010 and the reference medicinal 
product Lucentis®.  
LUBT010 has been developed as an investigational biosimilar of Lucentis® and has been found 
to be safe and well tolerated in pre-clinical program so far (similarity has been demonstrated 
through quality/ analytical and PCT studies). Lucentis® is a biologic approved by both US FDA 
and EMA with a well-established efficacy and safety profile, and therefore, chosen as a 
comparator in the current study. Randomization and double blinding methods will be used to 
avoid selection and evaluation bias. 
 
Neovascular (wet) AMD is a primary approved indication for Lucentis®; hence the patients 
with neovascular (wet) AMD will be enrolled in the study. The dose chosen for the study is 
0.5 mg intravitreal injection once a month, which is the approved and recommended dose of 
Lucentis® for this indication. 
 
Thus, to demonstrate the equivalence in efficacy and safety, this head-to-head study comparing 
LUBT010 with Lucentis® using double-blind, randomized controlled design is deemed most 
appropriate. 
6.2.1 
Choice of Study Population 
Indication: Neovascular AMD was the first indication for which ranibizumab was approved. 
Several studies have been conducted in this population and monotherapy with ranibizumab has 
become the standard of care for patients with CNV due to AMD regardless, of type and size of 
lesion; hence, patients with Neovascular AMD as study population have been selected. 
Age: Age-related macular degeneration occurs predominantly in the elderly. It is the leading 
cause of irreversible blindness among people who are 50 years of age or older in the developed 
world. Therefore, male and female patients ≥ 50 years with neovascular AMD have been 
selected for the study.  
Single Eye: Only one eye will be assessed as study eye in this trial. This is in line with pivotal 
clinical trials of innovator's ranibizumab. However, should AMD therapies required for other 
(non-study) eye during the study, the same can be allowed as per section 7.1.6.  
 
Considering these factors, the chosen study population is appropriate for the study. 
6.2.2 
Appropriateness of Measurements 
The primary and secondary endpoints chosen for the study are the ones used during 
development of Lucentis® and well accepted by various Regulatory agencies. Similarly, other 

 
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efficacy and safety parameters proposed are also in line with the conventional endpoints used 
in such type of studies. In line with requirements for biosimilar development, immunogenicity 
has also been included in this study. 
6.2.3 
Control Group 
The biosimilar development requires a comparative similarity with reference biologic at all 
steps of development. Accordingly, present study has reference biologic EU-approved 
Lucentis® as the active control arm. 
6.2.4 
Duration of Study 
Neovascular AMD, being a chronic progressive disease, patients are required to receive therapy 
for long duration. In addition, the landmark trials for ranibizumab (ANCHOR14, MARINA15 
and HARBOR16) have satisfactorily evaluated the primary endpoints with monthly injections 
for a period of 12 months. As per the MARINA trial results, more than 90% of patients in each 
treatment group remained in the study at 12 months, thus meeting the endpoints satisfactorily. 
Therefore, a treatment duration of 12 months is considered a relevant time period to assess the 
efficacy, safety, and immunogenicity in this study. 
 
6.3 
Schedule of Assessments 
The schedule of assessments to be performed at each visit is indicated in Table 1 (Schedule of 
Assessment). For details, refer Section 6.3.1 given below. 
6.3.1 
Detailed Study Assessments 
The objective of this clinical study is to study efficacy, safety, and immunogenicity of 
LUBT010 in comparison with Lucentis®.  
 
The following assessments will be performed at each study visit: 
6.3.1.1 
Screening Visit (Maximum 28 days) 
Screening procedures are as follows: 
• Obtain written informed consent as per regulatory requirement 
• Record demographic data (age, gender, race/ethnicity) 
• Record medical and surgical history (including ophthalmic history) 
• Record concomitant medications/treatment. 
• Vital signs assessment (temperature, Pulse, blood pressure [BP], respiratory rate [RR]) 
• Perform physical and systemic examination 
• Record weight 
• Perform ECG 
• AE assessment 
• Perform clinical laboratory assessment (hematology, biochemistry, and urinalysis) (and 
any other investigation, if deemed necessary by investigator) 
• Assessment of serological tests# for: human immunodeficiency virus (HIV), 
Hepatitis B virus (HBsAg), Hepatitis C virus (HCV), and syphilis (Rapid Plasma 
Reagin [RPR] test). 
• Follicle stimulating hormone (FSH) to be done in all females at screening. 

 
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Perform serum pregnancy test in females of childbearing potential (females who are 
not surgically sterile or menopausal). 
• Ophthalmic Examinations@: Unless otherwise stated these will be done for both the 
eyes 
− Refraction assessment 
− BCVA by ETDRS chart* 
− Ophthalmoscopy examination (indirect dilated) 
− Slit lamp examination 
− Intraocular pressure (IOP) measurement 
− Fluorescein angiography (FA)#: History of sensitivity to fluorescein dye to be 
checked before FA 
− OCT# 
@ Refraction and visual acuity testing should be done before pupil dilation and prior to 
other ophthalmic investigations. Only when the patient is eligible based on BCVA, the 
remaining investigations should be done. The order in which various procedures are 
performed may vary from clinic to clinic, provided the procedures are completed within 
screening period. 
# The period of 28 days can be relaxed up to two months for the tests marked # 
considering the longevity of the results for patients who may undergo rescreening (see 
Section 6.4.4). 
  
* BCVA measurements should begin in a sitting position using ETDRS chart (original 
Sloan letter chart or number chart) at a starting distance of 4 meters (for a subject, the 
same ETDRS chart used at screening should be used for all subsequent visit). A 
standardized ETDRS chart must be used at all participating sites to minimize the 
assessment discrepancy. Visual acuity measurements for each eye should be obtained 
by an ophthalmologist or a certified examiner.  
* Testing of visual acuity will be performed before the patient’s eyes are dilated and 
before other ophthalmic investigations like ophthalmoscopy, slit lamp, 
tonometry, FA or OCT if these procedures are to be carried out on the same day. 
• Assess patient eligibility against inclusion and exclusion criteria.  
• The eligible patients will be informed about Randomization visit and prescribed 
antimicrobial therapy (eg, systemic medications/ self-administer antimicrobial drops as 
prescribed by Investigator before and following each injection) 
 
6.3.1.2 
Treatment Period (12 months) 
6.3.1.2.1 Day 1 (Randomization and Ranibizumab First Dose Administration) 
Randomization should be performed within maximum of 28 days of screening. 
Day 1 (Predose) 
• Vital signs assessment  
• Urine pregnancy test (in females of childbearing potential [females who are not 
surgically sterile or menopausal]) 
• Perform physical and systemic examination 
• Confirmation of eligibility based on screening results and investigations done on Day 1 

 
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• Ophthalmic Examinations: Unless otherwise stated these will be done for both the eyes 
− Refraction assessment 
− BCVA using ETDRS* 
− Ophthalmoscopic examination  
− IOP measurement  
− Slit lamp examination 
• Interviewer administered NEI-VFQ-25 (baseline) 
• Immunogenicity (anti-drug antibody) assessment 
• Record changes in concomitant medication/treatment – if any 
• AE assessment 
• Randomization 
• Administer study medication in study eye only (if antimicrobial therapy taken as 
prescribed). 
 
Day 1 (Postdose) 
• Vital signs assessment  
• IOP measurement for study eye only at 60 min (± 30 min) post injection  
• Ophthalmoscopic examination in study eye only. 
• Observe for at least 60 min (± 30 min) postdose (post injection) 
• AE assessment 
Note: * notes of screening visit to be followed. 
 
6.3.1.2.2 Day 2 to 9 
The Day 2 -9 visit can be on any day from Day 2 to Day 9. 
• Vital signs assessment  
• IOP measurement 
• Ophthalmoscopic examination 
• Slit lamp examination 
• AE assessment 
• Inquire if antimicrobial therapy is taken as prescribed 
• Record changes in concomitant medication/treatment 
6.3.1.2.3 Visit Days (± 2 days): Day 31, 61, 91, 121, 151, 181, 211, 241, 271, and 301 
Pre dose 
• Vital signs assessment  
• Urine pregnancy test in females of childbearing potential  
• Perform physical and systemic examination 
• Record ECG (only at Day 181) 
• Perform clinical laboratory assessment (hematology, biochemistry and urinalysis) 
at Day 91, Day 181, and Day 271. 
• Ophthalmic Examinations: Unless otherwise stated these will be done for both the 
eyes 

 
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o Refraction assessment 
o BCVA using ETDRS* 
o Ophthalmoscopic examination 
o Slit lamp examination 
o IOP measurement (Obtained pretreatment for both eyes) 
• Interviewer administered NEI-VFQ-25 at Day 91 and Day 181. 
• Immunogenicity (anti-drug antibody) assessment at Day 31, Day 91, Day 181, and 
Day 271. 
• Record changes in concomitant medication/treatment 
• AE assessment 
• Administer study medication into study eye only (if antimicrobial therapy taken as 
prescribed). 
Postdose 
• Vital signs assessment 
• IOP measurement (Obtained at 60 min [± 30 min]) post injection in study eye only) 
• Ophthalmoscopic examination in study eye only 
• Observe for at least 60 min (± 30 min) postdose (post injection) 
• AE assessment 
Note: * notes of screening visit to be followed. 
 
6.3.1.2.4 Post injection visit / Telephonic Safety Assessment after injection 
administration 
A post injection visit/ telephonic safety assessment after injection administration will be done 
as deemed necessary by Investigator for the following: 
• AE assessment  
• Inquire if antimicrobial therapy is taken as prescribed 
• Record changes in concomitant medication/ treatment. 
 
6.3.1.2.5 Day 331 ± 2 days (EOT) 
Day 331 (Pre dose) 
• Vital signs assessment  
• Perform physical and systemic examination 
• Urine pregnancy test in females of childbearing potential 
• AE assessment 
• Record changes in concomitant medication/treatment 
• Ophthalmic Examinations: Unless otherwise stated these will be done for both the 
eyes 
o Refraction assessment 
o BCVA using ETDRS* 
o Ophthalmoscopic examination 
o Slit lamp examination 
o IOP measurement 

 
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• Administer study medication into study eye only (if antimicrobial therapy taken as 
prescribed). 
 
Day 331 (Post dose)  
• Vital signs assessment 
• IOP measurement (Obtained at 60 min [± 30 min]) post injection in study eye only) 
• Ophthalmoscopic examination (for study eye only) 
• Observe for at least 60 min (± 30 min) post dose (post injection) 
• AE assessment 
Note: * notes of screening visit to be followed. 
 
6.3.1.2.6 Day 360 ± 2 days (EOS/Early Discontinuation) 
The following procedures will be performed at Day 360 ± 2 days or at the time of 
withdrawal/discontinuation prior to 12 months of treatment: 
• Vital signs assessment 
• Perform physical and systemic examination 
• Perform clinical laboratory assessment (hematology, biochemistry, and urinalysis) 
• Perform Urine pregnancy test in females of childbearing potential only 
• Record ECG 
• AE assessment 
• Record changes in concomitant medication/treatment 
• Ophthalmic Examinations: Unless otherwise stated these will be done for both the 
eyes 
o Refraction assessment 
o BCVA using ETDRS* 
o Ophthalmoscopic examination 
o Slit lamp examination 
o IOP measurement 
• Immunogenicity (anti-drug antibody) assessment 
• Interviewer administered NEI-VFQ-25 
Note: * notes of screening visit to be followed. 
 
Post EOS visit or discontinued patients (anytime during study) may be shifted to appropriate 
standard therapy by the Investigator depending on the disease condition. 
 
6.4 
Selection of Study Population 
6.4.1 
Inclusion Criteria 
Patients satisfying all of the following criteria will be included in the study: 
 
1. 
Ambulatory male or female participants with age ≥ 50 years at the time of screening 
who are capable of understanding and giving written informed consent. 

 
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2. 
Primary or recurrent (anti-VEGF naïve) active CNV@ lesions involving the foveal 
center secondary to AMD in any one of the eyes.  
3. 
BCVA in the study eye, using ETDRS testing, between 20/40 and 20/200 (Snellen 
equivalent), both inclusive, before pupil dilation. 
4. 
Willingness and ability to undertake all scheduled visits and assessments. 
5. 
Females, who are of non-child bearing potential (surgically sterile or menopausal), OR, 
if of child bearing potential using effective birth control measures and non-pregnant and 
non-lactating during the study and 3 months after the last dose (Refer Section 2 - 
Definition of Terms). 
@Active CNV is defined as any leakage detected on FA  
6.4.2 
Exclusion Criteria 
Patients who meet any of the following criteria should be disqualified from entering the study: 
 
1. 
Known hypersensitivity to ranibizumab or any of the components of study medication. 
2. 
Known history of allergy to fluorescein dye. 
3. 
Scar, fibrosis, or atrophy involving the center of the fovea in the study eye as assessed 
by FA (confirmed by independent central reading center). 
4. 
Subretinal hemorrhage in the study eye that involves the center of the fovea, the size of 
the hemorrhage is either ≥ 50% of the total lesion area or ≥ 1-disc area in size (confirmed 
by independent central reading center). 
5. 
Total lesion area ≥ 12.0-disc areas (DA) in size (including blood, scars, and 
neovascularization) as assessed by FA in the study eye (confirmed by independent 
central reading center). 
6. 
History of vitrectomy, submacular surgery, or other surgical intervention for AMD in 
the study eye. 
7. 
Employees of clinical study sites, individuals directly involved with the conduct of the 
study or immediate family members thereof, prisoners, and persons who are legally 
institutionalized. 
8. 
Any other pathology involving the CNV lesion like retro-foveolar atrophy or permanent 
structural damage to fovea or fibrosis/ hemorrhage involving fovea > 50% of lesion area 
of study eye that can affect the efficacy of drug. 
9. 
Vitreous hemorrhage or history of rhegmatogenous retinal detachment, retinal pigment 
epithelial tears or rips involving the macula or macular hole (stage 1 to 4) in the study 
eye as assessed by FA (confirmed by independent central reading center). 
10. Uncontrolled glaucoma as evident by progressive damage to optic nerve or visual fields 
despite optimum therapy; or steroid-induced glaucoma with continued use of steroids 
that requires IOP-lowering treatment. 
11. History of serious complications following surgery in the study eye within 1 year prior 
to randomization. 
12. Previous treatment with intravenous or intravitreal anti-VEGF agents such as 
Bevacizumab, Ranibizumab, Aflibercept, Pegaptanib, Brolucizumab in either of the 
eyes. 
13. Previous external beam radiation or any laser therapy photocoagulation/ thermal laser 
thermotherapy/verteporfin photodynamic therapy (PDT) involving the foveal center in 
the study eye within 5 years prior to randomization. 

 
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14. Previous treatment with verteporfin photodynamic therapy (PDT), thermal laser, 
transpupillary thermotherapy (except subfoveal) in the study eye or use of protein kinase 
C inhibitors within 3 months prior to randomization. 
15. Previous treatment with intravitreal steroids (e.g., triamcinolone, anecortave acetate) in 
the study eye within 3 months prior to randomization. 
16. Previous treatment with intravitreal steroid implant (like Ozurdex®) within 6 months 
prior to randomization.  
17. Concurrent use of systemic anti-VEGF agents. 
18. Intraocular surgery (including cataract surgery) in the study eye within 3 months prior 
to randomization. 
19. Concurrent treatment with an investigational drug or device in the non-study eye. 
20. Previous participation in any studies of investigational drugs within 30 days or as 
prescribed in that study (whichever is later) preceding the initial study treatment. 
21. Patients who have DME and/or background or proliferative retinopathy will be 
excluded. Likewise, any with significant posterior subcapsular cataract (PSC) should be 
excluded 
22. CNV in the study eye due to causes other than AMD such as histoplasmosis, trauma, or 
pathological myopia etc. or CNV lesion not likely to respond to ranibizumab. 
23. Active or ongoing ocular infection (e.g. infectious conjunctivitis, keratitis, scleritis, or 
endophthalmitis) or severe inflammation in either of the eyes. 
24. Any concurrent intraocular condition in the study eye that could either require medical 
or surgical intervention during the 12 month study period or that could contribute to a 
loss (of at least 2 Snellen equivalent lines) of BCVA over the 12 months study period 
(e.g. progressive retinal disease or retinal pathology, cataract, glaucoma, uveitis, 
previous corneal transplant, the refractive error more than -8 diopters of myopia etc.). 
The decision regarding exclusion is to be based on the opinion of the Investigator. 
25. Any patient with cloudy media from any cause that prevents adequate visualization of 
the fundus with indirect ophthalmoscopy should be excluded. 
26. Patients with seropositivity for hepatitis B, hepatitis C, HIV antibody, syphilis tests or 
any immunodeficiency and/or immunosuppressive disease or active systemic infection. 
27. History or presence of concurrent systemic diseases or dysfunctions requiring 
significant medical/ surgical intervention during study period that might affect 
interpretation of the results or contraindicates the use of ranibizumab or render the 
patient at high risk for treatment complications based on the Investigator’s judgment 
such as: 
• Cardiovascular disease (e.g. stroke, myocardial infarction), uncontrolled 
respiratory, 
hepatic, 
renal, 
hematologic, 
gastrointestinal, 
endocrine, 
immunologic, dermatologic, neurologic (e.g. optic neuropathy), metabolic, 
pulmonary, autoimmune disease or psychiatric disease based on previous 
history and relevant reports of clinical examination, laboratory tests, or ECG 
etc. 
6.4.3 
Withdrawal and Discontinuation of Patients 
Patients may discontinue the study at any time without any penalty or loss of benefits to which 
the patient is otherwise entitled. For all patients withdrawn from the study, efforts will be made 
to ascertain the reason for withdrawal.  

 
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A withdrawn patient is one who meets any of the following withdrawal criteria stated below 
and whose study participation is discontinued. The reasons for patient withdrawal will be 
recorded in the electronic case report form (eCRF). 
In case of early discontinuations/ premature termination of the study all EOS investigations 
should be done on the day of termination as far as possible. 
Criteria for Withdrawal from Study: 
• The patient is not willing to continue participation in the study (withdraws consent). 
• Lost to follow-up 
General Criteria for Treatment Discontinuation 
• The patient needs emergency treatment or is unable to continue participation in the trial 
due to the exacerbation of their symptoms. 
• Inability of patient to comply with the Protocol for any reason. 
• The patient becomes pregnant during the study period. 
• In the opinion of the Investigator or sub-investigator, the patient should be discontinued 
due to AEs (including progressing complications) or safety reasons.  
• Other reasons due to which the patient should be discontinued, in the opinion of the 
Investigator or sub-investigator. 
Ocular Criteria: 
Treatment Discontinuation: 
Treatment should be discontinued in patients with rhegmatogenous retinal detachment or 
stage 1 to 4 macular holes. 
 
Dose Withholding Criteria: 
The dose should be withheld/postponed, and treatment should not be resumed earlier than the 
next scheduled treatment in the event of: 
• a decrease in best-corrected visual acuity (BCVA) of ≥30 letters in study eye compared 
with the last assessment of visual acuity; 
• an IOP of ≥30 mmHg before dosing; 
• a retinal break; 
• a subretinal hemorrhage involving the center of the fovea, or, if the size of the 
hemorrhage is ≥50%, of the total lesion area; 
• performed or planned intraocular surgery within the previous or next 28 days 
 
Based on OCT result, should the investigator decide to withhold an injection for potential safety 
concern, a pro-re-nata (PRN) or treat-and-extend regimen can be used. 
 
Any conditions given above or any other significant medical conditions (for example severe 
local or systemic infection or inflammation in either of the eyes) that can significantly affect 
efficacy or safety, in opinion of Investigator, will be discussed on case to case basis with the 
Sponsor and the patient can be withdrawn from the study, if justified. 
 
The treatment options will be discussed with all patients who have discontinued or completed 
study (EOS) and the patients will be continued on/ shifted to appropriate standard therapy by 
the Investigator depending on the disease condition.  

 
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6.4.4 
Rescreening of Patients 
Rescreening of a previously screen failed patient will be allowed for patients determined as 
screen failure due to inclusion and/or exclusion criteria that could transiently change and do 
not compromise the patient’s safety. Rescreens may occur until the sites are open for 
recruitment. Only one rescreen is allowed per patient. 
When a rescreen is authorized by the Sponsor or designee, patient is to be consented again and 
all screening procedures should be completed (for serology, FA and OCT please refer to 
Section 6.3.1.1). 
Patients who discontinue the study after randomization or after receiving study medication are 
not eligible for rescreening. 
6.4.5 
Other Patient Restrictions 
Patients may not participate in another clinical study that involves an investigational product 
(IP) during this study. 
Females patient currently pregnant or breast feeding or planning to conceive are not allowed 
to be included in the study. Female patients should refrain from becoming pregnant during the 
study period and should use effective contraception during the study and 3 months after the 
last dose of study drug. 
For concomitant medications/treatments which are restricted during the study, please see 
Section 7.1.6. 
6.4.6 
Early Termination of Study/ Site 
This study may be terminated at any time by the Sponsor if, the Investigator does not adhere 
to the protocol, non-performance or inability to follow the advices by the regulatory authorities 
of the country for global study, or in the Sponsor's judgment there are no further benefits to be 
achieved from the study or due to non-viability of the study on commercial grounds. In this 
event, the Sponsor will inform about the decision along with reason to the study Investigators, 
Institutions, ECs and all applicable regulatory authorities for the termination of study. 
 

 
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7 
TREATMENT OF PATIENTS AND INVESTIGATIONAL PRODUCT 
MANAGEMENT 
7.1 
Treatment of Patients 
7.1.1 
Dosages & Treatment Regimen 
Investigational products (LUBT010 & Lucentis®) will be administered as intravitreal injection 
in the study eye. All the patients will be randomized to one of the two arms viz. LUBT010 or 
Lucentis® arm, as per Table 2. 
 
Table 2: Doses and Treatment Regimen 
Treatment 
Arm 
Dose 
Route 
Duration & Frequency 
LUBT010 
0.5 mg  
Intravitreal injection in the 
study eye of patients 
Total 12 injections per patient; Once 
monthly (approximately 28 days) 
Lucentis® 
0.5 mg  
Intravitreal injection in the 
study eye of patients 
Total 12 injections per patient; Once 
monthly (approximately 28 days) 
 
7.1.2 
Precautions while Administering Investigational Product 
Investigational products (LUBT010 and Lucentis®) should be administered only by qualified 
ophthalmologists experienced in intravitreal injections. The interval between two doses should 
not be less than 28 days. 
 
Before treatment, the patient should be instructed to administer antimicrobial therapy (as 
prescribed by Investigator before and following each injection). The patient’s medical history 
for hypersensitivity reactions should be carefully evaluated prior to intravitreal injection. 
 
The intravitreal injection procedure should be carried out under controlled aseptic conditions. 
Adequate anesthesia and a broad-spectrum antimicrobial should be given prior to the injection. 
 
As with all medicinal products for parenteral use, IP should be inspected visually prior to 
administration.  
 
Prior to and 60 min (± 30 min) following the intravitreal injection, patients should be monitored 
for elevation in IOP using tonometry. Monitoring may also consist of a check for perfusion of 
the optic nerve head (Ophthalmoscopy) after the injection. Patients should also be monitored 
for and instructed to report without delay any symptoms suggestive of endophthalmitis 
following the injection. Details pertaining to preparation for administration of Investigational 
product is provided in Appendix A. 
7.1.3 
Randomization of Study Treatments 
The treatment arm (test or reference) for each patient during the study will be assigned 
according to randomization list. This randomization list will be prepared reviewed and finalized 
in a blinded manner and will not be accessible to the study team involved in the study conduct. 
The treatment will be assigned at the time of randomization, after confirming patient’s 

 
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eligibility. Patients will be randomized in a 1:1 ratio to either LUBT010 or Lucentis®. Patients 
who qualify for study randomization will have a unique randomization number. Randomization 
will be stratified by iris color (light colored, not light colored) to maintain treatment balance 
within strata. Randomization block size will be specified in the randomization plan and will 
not be shared with investigators. After completion of required number (600 patients), some 
patients who qualify in screening may not be enrolled in the study. 
7.1.4 
Blinding of Study Treatment 
This study will be performed in a double-blind manner. In order to maintain the double-blind 
status of the study, packaging of LUBT010 will have similar appearance to the Lucentis®. 
Investigator/ other members of staff involved in the study and patients will remain blinded to 
the treatment arm during the study. 
7.1.4.1 
Breaking the Blind for Safety Reason 
Randomization codes, indicating the treatment randomization for each randomized patient, will 
be available to the Investigator(s)/site, if required, as mentioned below. 
 
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment armor to meet 
regulatory requirements (e.g., in the case of SAE or death). In this case individual 
randomization codes, indicating the treatment arm for each randomized patient, can be made 
available to the Investigator(s). 
 
If possible, there should be a discussion among the Investigator and Lupin study team and/ or 
the medical expert prior to breaking the code. If the blind is broken, the date, time, and reason 
for unblinding must be recorded. If the treatment information is unblinded, the Investigator 
should document and report the action to Lupin. Patients will immediately be discontinued 
from the study by the Investigator and the EOS visit assessments will be performed. 
7.1.4.2 
Breaking the Blind for Regulatory Authorities 
If requested by regulatory agency, the blind can be broken and the unblinded safety information 
will be provided to the regulatory authority. In such cases, the patients can continue 
participation in the study. 
7.1.5 
Patient Compliance 
For this study-purpose the per protocol compliance to study medication will be defined as all 
those randomized patients who receive all the 12 intravitreal injections of 0.05 mL of 
10 mg/mL ranibizumab in the study eye. 
7.1.6 
Concomitant Therapy 
Prohibited Medications: Other therapies for the treatment of AMD, including but not limited 
to Verteporfin photodynamic therapy, Pegaptanib, Bevacizumab, Aflibercept or Brolucizumab 
will not be allowed in the study eye during the study. Anti-VEGF therapy, other than 
ranibizumab (approved innovator product) for treatment of exudative AMD in the respective 
country, will not be allowed in the non-study eye during the study. Other biologics will not be 
allowed during the study. Any other experimental therapy for treatment of AMD will not be 
allowed in study eye or non-study eye during the study. 

 
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Allowable Medications: Any other medications/ treatments required by the patient and not 
expected to interfere with study assessments will be allowed on a case-by-case basis and as 
deemed appropriate by the Investigator. Therapies like thermal laser and verteporfin PDT for 
AMD can be allowed in the non-study eye at the discretion of the Investigator. Anti-VEGF 
therapy [ranibizumab (approved innovator product) for treatment of exudative AMD in the 
respective country] can be administered in non-study eye as needed when deemed to be 
clinically justified in the opinion of the Investigator. Supplementation with antioxidant & 
minerals (non-investigational treatments) (e.g. lutein zeaxanthine or beta carotene, Vitamin C, 
E, and Zinc) can be allowed17. 
7.2 
IP MANAGEMENT 
7.2.1 
IP Dosage Form and Strength 
LUBT010/Lucentis® for Intravitreal injection is supplied as single-use vial designed to deliver 
0.05 mL of 10 mg/mL ranibizumab. The details of the study medications are given in Table 3. 
 
Table 3: IP Details 
Study 
Medication 
Dosage Form and Strength 
Sourced from 
LUBT010 
Supplied as single-use, 2-cc glass vial containing 
2.3 mg of ranibizumab in 0.23 mL solution 
designed to deliver 0.05 mL of 10 mg/mL 
ranibizumab, by intravitreal injection. 
Lupin Limited (Biotech Division), 
Gat No: 1156, Village Ghotawade, 
Taluka Mulshi, Pune, Maharashtra, 
India– 412115 
EU-approved 
Lucentis® 
Supplied as single-use, 2-cc glass vial containing 
2.3 mg of ranibizumab in 0.23 mL solution 
designed to deliver 0.05 mL of 10 mg/mL 
ranibizumab, by intravitreal injection. 
(Marketing Authorization Holder in 
UK)  
Novartis Europharm Limited 
Vista Building  
Elm Park, Merrion Road  
Dublin 4  
Ireland. 
 
7.2.2 
IP Packaging and Labelling 
A single-use, 2-cc glass vial (LUBT010 or Lucentis®) will be packaged individually in cartons 
along with syringes and needles. The packs will be labeled as per regulatory requirements. 
Each pack will have unique identification number. 
Each patient will be assigned a randomization number and IP pack containing either LUBT010 
or Lucentis® will be dispensed. 
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines. The label text will be translated into local language. The labels shall contain 
appropriate information as per the local regulatory requirements including but not limited to 
product content and strength, batch No, manufacture date, retest/ expiry date, storage 
information, route of administration, statements like “For Clinical Trial Purpose Only”. 
7.2.3 
Storage 
Investigational product (Ranibizumab) injection should be stored under refrigeration at 2º-8ºC 
(36º-46ºF) at all times. The product should be kept in the original carton to protect from light 

 
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until the time of use. Do Not Freeze. Prior to use, the unopened vial may be kept at room 
temperature (25°C) for up to 24 hrs. Do not use beyond the expiry date which is stated on the 
carton/vial. Do not use any pack if it is damaged. IP vials should be used once only, and any 
unused portion left in the vials should not be considered for use. 
7.3 
IP Supply, Handling and Accountability 
The Sponsor/ designee will arrange for the supply, handling, and management of IPs. The 
Sponsor/ designee will supply sufficient quantity of IPs, for administration to randomized 
patients at each site. Blinded IP will be shipped under appropriate storage conditions to the 
Investigator sites. 
The designated study personnel must take the responsibility to keep a record of the IP 
management.  
Sites will receive IP with appropriate documents and store according to the storage 
requirements. Adequate records of IP for receipt, accountability, usage and disposal, or return 
to Sponsor will be maintained at respective Investigator site. Investigational product will be 
administered to eligible patients according to randomization schedule. 
 
Pharmacist/ designated study personnel will dispense the IP for administration. The unused IP 
will be kept in their original containers. The sites will return any unused IP to the Sponsor or 
destroy on site (as mutually agreed between Sponsor and sites), once the site’s monitor has 
reviewed and confirmed drug accountability, or at the end of the study. 
 
Used IP vials should also be kept in the original packing and this should also be returned/ 
destroyed on site (as mutually agreed) to Sponsor after confirmed drug accountability by site 
monitor. 
 
The IPs should not be used for purposes other than those conforming to this protocol. 

 
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8 
ASSESSMENT OF EFFICACY 
8.1 
Efficacy Endpoints 
Primary Efficacy Endpoint: 
Mean change in BCVA from baseline in the study eye at the end of 12 months, assessed 
with the ETDRS chart. 
 
Secondary Efficacy Endpoints:  
• Mean change in BCVA from baseline in the study eye at the end of 3 months, assessed 
with the ETDRS chart. 
• Mean change in BCVA from baseline in the study eye at the end of 6 and 9 months, 
assessed with the ETDRS chart. 
 
Exploratory Endpoint:  
• Mean change from baseline in NEI-VFQ-25 Version 2000 (interviewer administered) 
scores at of 3, 6, and 12 months. 
8.2 
Efficacy Variables 
Mean change in BCVA from baseline in the study eye by ETDRS chart will be measured as 
primary and secondary endpoints. BCVA is measured by the number of letters a patient could 
correctly read on an eye chart; hence an increased score indicates improvement in acuity. 
 
For this study the ETDRS chart (including original Sloan letter chart or number chart) will be 
used for visual acuity measurement. Standard procedures will be followed for ETDRS testing 
across sites. The details of the testing procedures will be described in a separate procedures’ 
manual. It is must that testing is done prior to dilating eyes with refraction error corrected with 
lenses. The ETDRS testing will be standardized and made uniform across sites. 
 
The NEI-VFQ-25 Version 2000 will be administered by the interviewer at baseline (Day 1), 3, 
6, and 12 months, which is a measure of subjective response and compliments the objective 
findings of BCVA. 

 
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9 
ASSESSMENT OF SAFETY 
Following safety parameters will be assessed, 
 
• AE assessment, ocular and non-ocular (as per National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE V5])  
• Ophthalmic examination  
• Physical and systemic examination  
• Vital signs  
• ECGs  
• Laboratory parameters: Blood (hematology and biochemistry) and urinalysis 
9.1 
Adverse Events 
9.1.1 
Definitions 
The definitions for AEs and SAEs are given below. It is of the utmost importance that staff 
involved in the study is familiar with the content of this section. The Principal Investigator is 
responsible for ensuring this. 
9.1.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore, be any unfavorable and unintended sign, 
symptom, or disease (including intercurrent illness), deterioration of a pre-existing illness, 
accident, any suspected drug reaction, or a clinically relevant change of laboratory values 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product and/or study treatment. 
 
A treatment-emergent AE (TEAE) will be defined as an AE that begins or worsens in severity 
after at least one dose of study drug has been administered. 
 
See Section 9.7 below for the instances where a pregnancy should be reported as an AE. 
9.1.1.2 
Serious Adverse Event 
An SAE is defined as, any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an event that, had it occurred in a more severe form, might have caused 
death. 
• Requires in-patient hospitalization or prolongation of hospitalization  
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Consists of any other medically important condition. 
 

 
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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.’ 
9.1.2 
Recording and Collection of Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) 
derived from spontaneous, unsolicited reports of patients, by observation, and by routine open 
questions. 
AE reporting will extend from date of informed consent until completion of the final visit 
(EOS). Any ongoing AE at EOS visit (Day 360 ± 2 days) should be followed until the outcome 
is evident and resolved, clinically stabilized or a plausible explanation has been found. 
Pre-existing diseases including deranged laboratory values (before participating in the study) 
are not considered to be AEs, unless the disease worsens during the study period. Concomitant 
diseases detected during screening or prior to randomization will be recorded in the medical 
history eCRF.  
 
Signs and symptoms clearly associated with the disease under study (including symptoms of 
disease progression) should be reported as AEs if they are newly emergent (i.e., findings not 
previously observed in the patients), or are determined by the Investigator as severe or a 
worsening, or if the Investigator considers deterioration of disease-related signs and symptoms 
to be caused directly by the study drug. 
 
Abnormal laboratory values/ ECGs/ vital signs/ ophthalmic/ physical &systemic examination 
should be reported as AEs only if the Investigator considers the abnormality as clinically 
relevant or significant or believes that the abnormality should be reported as an AE. 
 
Any dose (and associated symptoms) given to the patient that exceeds the dose prescribed to 
the patient has, at a minimum, to be recorded as a non-serious AE in the patient file and eCRF. 
Any case of overdose leading to an AE or SAE should be reported to Medical Monitor 
according to reporting requirements. In case of an accidental overdose, the patient should be 
monitored by the Investigator for any adverse clinical events including IOP, as deemed 
necessary by the Investigator. 
 
After completion of all scheduled visit assessments, the Investigator must document any AEs 
arising from these assessments. In case of an SAE, the Investigator must also complete an SAE 
report form and report it to safety contact, as described in Section 9.1.3.3. 
 
All AEs will be recorded in eCRF regardless of the causal relationship to the study drug. 
 
All AE records should contain AE term/ AE diagnosis, date of onset, severity, relationship to 
the study drug, outcome, date of recovery or outcome, action taken with respect to study drug, 
action taken with AE, AE leading to discontinuation of patient from study, and whether the 
event is classified as serious. 

 
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The categorization of action taken with IP, outcome and action taken for AE is described below: 
 
Categories of Actions 
Taken with IP 
Categories of Outcome* 
Categories of action taken 
for AE 
• 
Dose Delayed 
• 
Drug withdrawn temporarily 
• 
Drug withdrawn 
permanently 
• 
Unknown 
• 
Not applicable 
• 
Recovered/Resolved 
• 
Recovered/Resolved with sequelae 
• 
Recovering/Resolving 
• 
Not Recovered 
• 
Fatal 
• 
Unknown 
• 
None 
• 
Medication 
• 
Hospitalization 
• 
Non-drug treatment 
• 
Patient withdrawn 
• 
Other 
*If there is more than one AE, only the AE leading to death will be attributed with a fatal outcome.  
 
In cases where multiple symptoms and signs can be described as one diagnosis (disease), the 
name of the diagnosis is reported as the name of the AE. 
For example, running nose, cough, and sore throat: The 3 symptoms can be described as a 
series of symptoms of "common cold" 
⇒ Common Cold or Upper Respiratory Tract Infection  
 
The Investigator must continue to follow-up the patient with all AEs regardless of the causal 
relationship to the study drug until the AE has resolved or until the condition stabilizes to an 
acceptable level or is determined to pose no issue, or until follow-up is no longer feasible. 
 
9.1.3 
Evaluation of Adverse Events 
Each AE is evaluated depending on the following categories by the Investigator. 
 
9.1.3.1 
Definition of severity of an AE 
Wherever possible, all observed AEs will be graded using the CTCAE version 5.0. The severity 
of the AE shall be classified using the following grading. 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to an AE. 
Semicolon (;) indicates “or”. 
 
Record the maximum intensity for AE occurring frequently than once a day. If the intensity 
category changes over a number of days, then those changes should be recorded as a new AE 
with the onset date of the new intensity. 
 

 
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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 9.1.1.2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may 
be considered severe nausea, but not an SAE. On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE. 
9.1.3.2 
Relationship to the Study Drug 
The assessment of the relationship of an AE to the administration of study drug is based on the 
presence or absence of a “reasonable possibility” that investigational drug has caused the AE. 
An AE is considered to be “related” to the study medication if a causal relationship between 
the IP and an AE is at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
An AE related to the study drug is referred to as an adverse drug reaction (ADR). 
 
The expression “reasonable causal relationship” is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship (ICH E2A guideline) based on 
relationship to time of onset and drug administration, temporary withdrawal, not attributable 
to any other drug or condition, dechallenge and rechallenge information as available. 
 
The causal relationship between an AE and the study drug will be defined as below: 
  
Not Related: When the AE is definitely caused by the patient's clinical state, or the study 
procedure/ conditions or other concomitant drugs. 
 
Unlikely Related: When the temporal association between the AE and the drug is such that 
the drug is not likely to have any reasonable association with the AE. 
 
Possibly Related: When the AE follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by the patient's clinical state or the study 
procedures/ conditions. 
 
Related: When the AE follows a reasonable temporal sequence from the time of drug 
administration, abates upon discontinuation of the drug and reappears when the drug is 
reintroduced. 
 
In final evaluation for reporting, the relationship will be converted into “Binary 
Determination”. ‘Not Related’ and ‘Unlikely Related’ will be clubbed into “Not Related” and 
‘Possibly Related’ and ‘Related’ will be clubbed into “Related” for final reporting purpose. 
9.1.3.3 
Reporting of Serious Adverse Events 
All SAEs occurring after the time of informed consent until the final visit (Day 360 visit) must 
be reported. 
 
All SAEs should be reported by the Investigator to the Safety Contact via Email (at 
clinicalsafety@lupin.com) or telephone within 24 hours, regardless of the causal relationship 
with the IPs (following knowledge of the SAE). After receiving reports of the SAEs, the Safety 
Contact should communicate with the Investigator to get additional information for evaluation 
of SAEs. 

 
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The Investigator is responsible for reporting SAE (initial report, analyzed report as well as 
follow-up information) to the Ethics Committee (EC) and/or applicable regulatory authority as 
per applicable local regulatory requirements of participant countries. All SAEs shall be 
reported by Investigator/ Sponsor/ Sponsor designee as per applicable regulatory requirements. 
 
The Details of Safety Contact: 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
  
 
9.1.3.4 
Follow – Up of Serious Adverse Events 
The Investigator must continue to follow the patient until the SAE has resolved or until the 
condition stabilizes to an acceptable level or is determined to pose no issue, or until follow-up 
is no longer feasible. Any ongoing SAE at EOS visit (Day 360 ± 2 days) should be followed 
until the outcome is evident and resolved, clinically stabilized or a plausible explanation has 
been found. 
9.1.3.5 
Suspected Unexpected Serious Adverse Reactions  
An SAE that is also an unexpected ADR is called a Suspected Unexpected Serious Adverse 
Drug Reaction (SUSAR). Unexpected adverse reactions are adverse reactions, of which the 
nature, or severity, is not consistent with the recent IB.  
 
Suspected Unexpected Serious Adverse Drug Reactions will be reported in compliance with 
regulatory reporting requirements of participating countries. The details of reporting of SAE, 
significant AEs and SUSARs will be captured in the Safety Monitoring Plan (SMP). 
9.1.4 
Ocular AEs 
9.1.4.1 
Worsening of Symptoms and Signs of Choroidal Neovascularization 
Worsening of symptoms and signs of CNV should be recorded as an AE or SAE only if judged 
by the Investigator to have unexpectedly worsened in severity and/or frequency or changed in 
nature at any time during the study. When recording an unanticipated worsening of CNV, it is 
important to convey why the development was unexpected. For significant Ophthalmic AEs 
reportable as SAEs refer the criteria below (Section 9.1.4.2). 
 
Developing symptoms and signs that are consistent with the natural history of CNV secondary 
to AMD is not considered a reportable adverse event in this study. 
 

 
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For example, moderate loss of visual acuity over time, expansion of the size of the lesion, and 
increased intraretinal or subretinal fluid are common developments associated with AMD. 
Such information is recorded in the medical history but are not reportable AEs. 
9.1.4.2 
Vision Threatening Serious Adverse Events 
An AE is considered to be vision-threatening and is a reportable SAE, if it meets one or more 
of the following criteria: 
• Rhegmatogenous retinal detachment or stage 1 to 4 macular holes. 
• It requires surgical intervention (e.g., conventional surgery, vitreous tap or biopsy with 
intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to prevent 
permanent loss of sight. 
• Any ophthalmic symptom/ eye disorder other than the above that has sight threatening 
consequences, requiring urgent intervention e.g. blindness in the affected eye. 
9.1.5 
Non-Ocular AEs due to VEGF inhibition 
9.1.5.1 
Arterial Thromboembolic events 
Arterial thromboembolic events like myocardial infarction, stroke should be recorded as 
AEs/SAEs as applicable, as there is a theoretical risk of these events following intravitreal use 
of VEGF inhibitors.  
9.2 
Ophthalmic Examination 
Ophthalmic examinations will be done on screening and after screening according to the 
schedule of procedures described in Table 1. 
9.3 
Physical and Systemic Examination 
A physical and systemic examination will be performed at the time of screening and after 
screening according to the schedule of procedures described in Table 1. 
 
Physical examinations will include, but are not limited to, the below items: 
 
General findings, HEENT exam (head, eyes, ears, nose, and throat), assessment of respiratory, 
cardiovascular, gastrointestinal, nervous, musculoskeletal, and renal/ urinary systems, lymph 
nodes, and dermatologic examination (including skin appendages) and other findings/ physical 
conditions of note. Any abnormal findings will be evaluated for clinical significance. 
9.4 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, and body temperature will be 
measured at screening and after screening according to the Schedule of Assessment described 
in Table 1. Any abnormal findings will be evaluated for clinical significance. 
9.5 
Electrocardiogram Assessments 
A 12-lead ECG will be performed at screening and after screening according to the Schedule 
of Assessment described in Table 1. It will be recorded by qualified personnel after the patient 
has been resting in the supine position for at least 3 min. Any abnormal findings will be 
evaluated for clinical significance. 

 
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9.6 
Clinical Laboratory Examinations 
Hematology tests, biochemistry tests including serological test (HIV, HBV, HCV, and syphilis) 
and urine analysis tests for safety assessment will be performed at screening and after screening 
according to the Schedule of Assessment described in Table 1. 
The list of tests for safety laboratory assessment is shown in Table 4. 
 
Urine Pregnancy test for females of childbearing potential will be performed at Day 1, prior to 
each dosing, and at EOS. Urine pregnancy test should be performed by the female patients 
themselves and the results reported to site during the visit.  
Serum pregnancy test for females of childbearing potential will be performed at screening. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or if required by local regulations.  
9.6.1 
Central Laboratory Samples 
Sample collection and handling for laboratory tests will be conducted in accordance with the 
laboratory manuals and collected samples will be sent to the central laboratory. Not more than 
280 mL of blood per patient will be collected during this study for planned study assessments 
(until EOS). 
Table 4: Clinical Laboratory 
Hematology 
Biochemistry 
Urinalysis 
Serology 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count  
White blood cell count 
Differential white blood 
cell count: 
Neutrophils 
Basophils  
Eosinophils  
Lymphocytes 
Monocytes 
 
Albumin 
Globulin 
Total protein 
Alkaline 
phosphatase 
ALT 
AST 
Bilirubin (total,  
Direct & Indirect) 
BUN 
Urea 
Uric Acid 
Creatinine 
Random Glucose 
Serum pregnancy* 
FSH** 
Routine Examination 
Color 
Appearance 
pH 
Urobilinogen 
Occult blood 
Glucose 
Protein 
Ketone 
Specific gravity 
 
Microscopic Examination 
(if abnormality is suspected) 
Red Blood Cells 
Pus cells  
Crystals  
Cast 
Bacteria 
Yeast 
Other  
HIV 
HBV (HBsAg) 
HCV 
Syphilis (RPR)# 
*Serum pregnancy test will be done in females of childbearing potential. 
**Follicle stimulating hormone (FSH) (in all females at screening visit). 
# Additional confirmatory test may be performed in RPR reactive cases, due to suspected false positivity. 
Note: Urine pregnancy test (UPT) to be performed by the female patients themselves and the results reported 
to site. However, it can be repeated anytime in local/ central laboratory when pregnancy is suspected in any 
female patient. 
 

 
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Any clinical test results outside the reference value range will be evaluated for clinical 
significance. After dosing, laboratory abnormalities considered by the Investigator to have 
worsened compared to that prior to dosing will be recorded as AEs. 
9.7 
Pregnancy 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions. Hospitalization for normal delivery of a healthy newborn should not be 
considered an SAE. 
If a pregnancy or a positive pregnancy test is reported for a patient during study participation, 
the study drug must be immediately discontinued. 
Pregnancies occurring during the study until EOS must be reported. All pregnancies must be 
reported to the Sponsor within 24 hours after becoming aware of the pregnancy, using the initial 
pregnancy report form. The Investigator should counsel the patient; discuss the risks of 
continuing with the pregnancy and possible effects on the fetus. The Investigator must 
follow-up and document the course and outcome of all pregnancies, even if the patient was 
discontinued from the study or if the study has finished. 
 
All outcomes of pregnancy must be reported by the Investigator to the Sponsor on the 
pregnancy outcome report form within 30 days after he/she becomes aware of the outcome. 
 
Any SAE that occurs during a pregnancy must be recorded on the SAE report form (e.g. 
maternal serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, 
stillbirth, neonatal death, congenital anomaly, or birth defects) and reported in accordance with 
the procedure for reporting of SAEs. 

 
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10 
ASSESSMENT OF IMMUNOGENICITY 
10.1 
Anti-Drug Antibodies 
Immunogenicity will be assessed in patients on Day 1 (pre-dose) and thereafter as per Table 1. 
Samples for immunogenicity will be collected prior to dosing. An appropriate and validated 
method will be used for assessment of anti-drug antibodies. 
Note: A tiered approach will be followed for assessing antibody formation in response to IP 
administration. All samples will be screened for occurrence of binding antibodies. Samples that 
test positive will be subjected to a confirmatory assay. Samples that are positive on 
confirmatory assay will further be tested for assessing the titer and neutralizing potential. 
10.1.1 
Collection, Handling, and Analysis of Immunogenicity Samples 
Blood samples will be collected using a blood collection tube by venipuncture. 
 
Anti-drug antibodies will be analyzed using a validated method, at a laboratory designated for 
analysis of immunogenicity samples. 
 
The sample handling, transportation, storage, and processing of will be carried out according 
to Laboratory Manual. 
 

 
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11 
STATISTICAL EVALUATION 
11.1 
Sample Size and Power 
Sample Size for Change from Baseline in BCVA at Month 12 (Primary Endpoint) 
In order to determine the margin for equivalence, a meta-analysis based on current literature in 
AMD patients was performed. Data included were data from the 0.5 mg ranibizumab and the 
SHAM treatment groups. Studies included were in the original regulatory filing. Change from 
baseline to Month 12 of BCVA was used as the endpoint. A mean difference of 17.9 letters 
[95% CI 15.7-20.0] was found. Heterogeneity was assessed and was not found to be statistically 
significant (p=0.5752), and hence the fixed-effect model was used to construct the confidence 
interval. Based on a lower confidence bound of 15.7 letters, an equivalence margin of 4 letters 
preserved 74.5% of the treatment effect. The pooled standard deviation (SD) from the 
ranibizumab arms is 14.5 letters. 
Figure 2: Meta-Analysis 
 
A sample size of 558 evaluable patients allocated in 1:1 ratio (279 per treatment) at (two-sided) 
5% level of significance and 80% power will be required to test the therapeutic equivalence 
between Lupin’s LUBT010 verses Lucentis® at equivalence margin of 4 letters and SD of 
14.5 letters. 
 
Sample Size 
Assuming a dropout rate of 7%, 600 patients will be randomized so as get approximately 
558 evaluable patients in a 1:1 ratio between the two treatment arms (279 in each arm) to yield 
80% power for the mean change from baseline in BCVA at the end of 12 months.  
11.2 
Statistical Methods 
This section describes the statistical analysis as it is foreseen at the time of planning the study. 
Any major deviations from this plan, the reasons for such deviations, and all alternative or 
additional statistical analyses will be provided in a Statistical Analysis Plan (SAP) as 
applicable. 
Continuous variables will be presented in summary statistics of number of patients (n), mean, 
SD, median, minimum and maximum by appropriate group and time point. Categorical 
variables will be described using the frequency count of the events, and the number and 
proportion of responding patients. 
 

 
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The study being conducted at multiple sites, the data collected from individual sites will be 
pooled for analysis. Detailed listings will be produced for all relevant efficacy, safety, and 
immunogenicity data by treatment and by visits wherever applicable. 
Detailed methodology on summary and statistical analysis of the data collected in this study 
will be provided in the SAP which will be finalized prior to the database lock. 
11.2.1 
Significance Level and Confidence Interval 
All statistical tests will be two-sided and evaluated at a 5% level of significance. 
 
11.2.2 
Criteria for Equivalence 
Equivalence will be determined based on the change from baseline in BCVA at Month 12. An 
equivalence margin of 4 letters will be used. If the 90%# (2-sided) confidence interval for the 
difference in means in change from baseline at month 12 is wholly within the equivalence 
margin (−4, 4), then the null hypothesis 
 
H0: µ1−µ2≤−4  or  µ1−µ2≥ 4 
 
will be rejected in favor of the alternative hypothesis 
 
HA: |µ1−µ2|< 4, 
 
where µ1 represents the population mean change from baseline for patients treated with 
LUBT010, and µ2 represents the population mean change from baseline for patients treated 
with Lucentis®. (# As generally required by US Food and Drug Administration [FDA]) 
 
Similar methodology will be used with 95%## CI for difference. Thus, if 95% (2-sided) 
confidence interval, lies wholly within the equivalence margin (-4, 4), then the null hypothesis 
will be rejected. (## As generally required by the European Medicines Agency [EMA].) 
 
11.3 
Handling of Missing Data 
There are many possible reasons for missing data (eg, patient refusal to continue in the study, 
treatment failures and successes, adverse events etc.), not all of which are related to the IP. 
Different degrees of data incompleteness can occur i.e. measurements may be available only 
at baseline or may be missed for one or several follow-up assessments. Such missing data will 
be handled by using appropriate methods. These methodologies will be described in detail in 
the SAP. 
11.4 
Patient Disposition 
A detailed description of the patient disposition will be provided in the clinical study report. It 
will include the number of patients screened, randomized, completed, as well as the number of 
dropouts, with reasons for discontinuation and major protocol deviations. All patients entered 
in the study will be accounted for this. 

 
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11.5 
Baseline and Demographic Characteristics 
Categorical data will be summarized as frequencies, percentages and continuous data as 
descriptive statistics (number of patients, mean, SD, median, minimum value, and maximum 
value). Demographic data will include age, gender, race, ethnicity, weight, and disease specific 
baseline characteristics that will be detailed in SAP. 
 
11.6 
Analysis Sets 
The analysis sets are described below.  
11.6.1 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all randomized patients who have received at least 
one dose of study drug with a baseline and one post baseline BCVA measurement. The FAS 
will be the primary population for analysis. 
 
11.6.2 
Per Protocol Analysis Set (PPS) 
The Per Protocol Analysis Set will include all patients in the FAS without any major protocol 
deviation.  
 
11.6.3 
Safety Analysis Set (SAF) 
Safety Analysis Set will include all patients who receive at least one dose of study medication. 
SAF will be used for all safety analyses. 
 
11.6.4 
Immunogenicity Analysis Set (IGS) 
The immunogenicity analysis set (IGS) will include all patients who receive at least one dose 
of study medication and subsequently provide a valid post-baseline immunogenicity result. 
 
11.7 
Efficacy Analysis 
11.7.1 
Primary Efficacy Endpoint 
The primary endpoint is mean change in BCVA from baseline in the study eye at the end of 
12 months, assessed with the ETDRS chart. 
The primary endpoint will be analyzed using ANCOVA model with fixed-effect treatment, 
and baseline BCVA as covariate. 
 
Denote the population parameter for the mean change from baseline in BCVA by θR for 
LUBT010 arm, and by θL for Lucentis® arm, expressed in letters. The hypothesis to be tested 
will be 
H0:  θR − θL ≤  −4 or 4 ≤ θR − θL versus HA:  −4 < θR − θL < 4. 
The hypothesis will be tested using the two-sided 90% confidence interval for the difference 
as accepted by US FDA. If the 90% confidence interval lies wholly between -4 and 4, then the 

 
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null hypothesis will be rejected. The confidence interval will be constructed using a two-sample 
t-test. 
 
Similar methodology will be used with 95% CI of mean difference for EMA. Thus, if 95% 
(2-sided) confidence interval, lies wholly within the equivalence margin (-4, 4), then the null 
hypothesis will be rejected. 
 
Missing data in the primary endpoint will be imputed by multiple imputation approach under 
the assumption of outcome is Missing At Random (MAR). The MAR assumption will be 
implemented using ANCOVA model by repeated imputation of missing values in primary 
endpoint. For this assumption, missing outcomes are modeled using observations from a 
patient’s own treatment arm. Thus, MAR would tend to reflect in the missing data any observed 
differences between treatment groups and is appropriately conservative for the objective of 
assessing equivalence. Then, to assess the robustness of MAR assumption in primary analysis, 
the sensitivity analysis via tipping point approachunder the Missing Not At Random (MNAR) 
assumption will be performed. 
Details will be provided in the SAP, which will be finalized and signed prior to database lock 
and unblinding 
11.7.2 
Secondary Efficacy Endpoints 
The secondary endpoints for this study are: 
• Mean change in BCVA from baseline in the study eye at the end of 3 months, assessed 
with the ETDRS chart. 
• Mean change in BCVA from baseline in the study eye at the end of 6 and 9 months, 
assessed with the ETDRS chart. 
 
All efficacy endpoints will be summarized descriptively by treatment and time point. 
Continuous endpoints will be presented using sample size, mean, SD, minimum, median, and 
maximum, and categorical will be presented using sample size and percentages. 
Summarization will be presented for both PPS and FAS. For these summaries, no imputation 
of missing data will be used. 
 
11.7.3 
Exploratory Endpoint 
The exploratory endpoint for the study is: 
• Mean change from baseline in NEI-VFQ-25 Version 2000 (interviewer administered) 
scores at 3, 6, and 12 months. 
 
The NEI-VFQ-25, Version 2000, will be administered by the interviewer at baseline, 3, 6, and 
12 months, and the scores obtained will be summarized using number of patients, mean, SD, 
minimum, median, and maximum, by treatment group and scheduled visit. No imputation will 
be performed. Data from exploratory endpoints will be summarized using appropriate 
descriptive statistics and also listed as applicable. Details will be provided in SAP. 
 

 
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11.8 
Safety Analysis 
The safety data will be summarized and listed. Detailed statistical methodology will be 
described in SAP. 
11.8.1 
Parameters for Assessment of Safety 
• AE assessment, ocular and non-ocular 
• Ophthalmic examination 
• Physical and systemic examination  
• Vital signs  
• ECGs  
• Laboratory parameters: Blood (hematology and biochemistry) and urinalysis 
11.8.1.1 
Adverse Events 
All AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) according to 
the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or higher. Events 
will be classified as TEAEs if they start on or after the date of the first dose of study medication. 
The number of AEs and the number and percentage of patients experiencing AEs will be 
summarized by severity and relationship to the study medication. SAEs and AEs leading to 
premature study discontinuation will be summarized. The corresponding listings will be 
provided. Study drug injection sites will be assessed for injection site reactions/ inflammatory 
reactions at each study visit. 
11.8.1.2 
Ophthalmic Examination 
Ophthalmic examination findings will be summarized using appropriate descriptive statistics 
and also listed as applicable. 
11.8.1.3 
Physical & Systemic Examinations and Electrocardiogram Measurements 
Changes in the physical and systemic examinations and 12-lead ECG findings from screening 
to the end of IP will be listed. 
11.8.1.4 
Laboratory Data 
Descriptive statistics will be performed for laboratory parameters at each scheduled visit and 
for the changes from baseline, by treatment and time point. For continuous outcomes, 
summaries will include sample size, mean, SD, minimum, median, and maximum. Abnormal 
values in each treatment arm will be determined and listed using reference ranges provided by 
the central laboratory. All laboratory results will be listed, including data from the unscheduled 
visits. 
11.8.1.5 
Vital Signs 
Changes in vital signs (pulse rate, respiratory rate, body temperature, blood pressure) from 
baseline to vital signs assessment at subsequent visits will be summarized. The corresponding 
listing will be provided. 

 
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11.8.1.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO-Drug Dictionary 
classification and a listing will be prepared. All medications that are ongoing during the study 
and concomitant medications received after randomization will be summarized. 
11.8.1.7 
Analysis of Immunogenicity 
The immunogenicity data reflect the proportion of patients whose test results will be considered 
positive for antibodies to ranibizumab in immunoassays. The incidence of immunogenicity to 
ranibizumab will be tested between treatment arms on Day 1 and at the end of 1, 3, 6, 9, and 
12 months.  
A similar analysis will be performed for the proportion of patients with positive neutralizing 
antibodies to ranibizumab. 
In this study, if at least one sample tests positive in the validated method during this study, the 
patient is evaluated as a positive patient. 
Details about analysis of immunogenicity will be provided in the SAP. 
11.8.1.8 
Extent of Exposure 
Study compliance and the extent of exposure to the study medication will be summarized. 
11.8.1.9 
Patient Discontinuation 
All patients who discontinued from treatment and study will be listed and the reasons for 
discontinuation will be tabulated. 

 
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12 
DATA MANAGEMENT 
12.1 
Data Handling 
Data will be recorded at the site in source documents and will be transcribed in the eCRFs 
promptly in English and the Investigator shall verify the accuracy of data in the eCRF. 
 
The Investigator shall maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination including 
ophthalmic examination reports. 
 
Data from external sources (such as laboratory data) will be appropriately handled into the 
database. Medical information will be coded using MedDRA and WHO Drug Dictionary. 
 
The monitor assigned to the site will verify the data recorded in the eCRF with source 
documents. The monitor confirms whether reporting is complete and that there are no 
contradictions by inspecting the eCRF. The monitor checks for contradictions between 
documents based on data in the eCRF by source data verification. All corrections or changes 
made to any study data must be appropriately tracked in an audit trail in the eCRF system. 
 

 
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13 
CLINICAL STUDY MANAGEMENT 
13.1 
Conduct of the Study 
Lupin will conduct the study according to written standard operating procedures to ensure that 
the study is conducted, and data are generated, documented, and reported in compliance with 
the protocol, ICH Good Clinical Practice (GCP) E6 (R2) and applicable regulatory 
requirements. 
13.2 
Direct Access to Source Data 
During the course of the study, the monitor will review protocol compliance, compare eCRFs 
and individual patient medical records, assess drug accountability records and ensure that the 
study is being conducted according to applicable regulatory requirements. The review of 
medical records will be performed in a manner to ensure that patient confidentiality is 
maintained. 
 
A review of the eCRFs for completeness, accuracy, legibility, timeliness, and clarity, as well 
as with source documents will be required to monitor the progress of the study. Moreover, the 
applicable regulatory authorities, Institutional Review Boards (IRBs), Institutional Ethics 
Committees (IECs) and/ or the Sponsor designated Clinical Quality Assurance team may 
perform source data checks and/ or on-site audits/ inspections to confirm the validity of the 
trial conduct and the integrity of data collected. Direct access to the source data will be required 
for these inspections and audits; these will be carried out giving due consideration to data 
protection and medical confidentiality. The Investigator must ensure provision of the necessary 
support to the Sponsor/ Sponsor’s representative, regulatory or IEC/IRBs at all times.  
13.3 
Amendments to the Protocol 
Important changes to the protocol and study design require a mutual agreement between the 
Investigator and Sponsor and will be effective following approval of the IRB/IEC and 
regulatory authorities (as necessary). These changes are to be described in the revised protocol 
and a list of changes detailing the pre-change and post-change versions will be prepared. 
13.4 
Guidance and Supervision of Sub-Investigators 
The Principal Investigator shall maintain the list of appropriately qualified sub-investigators 
and study support staff (e.g. pharmacists, nurses and other staff) to whom significant 
trial-related duties have been delegated. 
 
The Principal Investigator shall ensure that all sub-investigators and study support staff 
participating in the trial are adequately trained on the protocol, the IP(s) and their trial-related 
duties and functions and they are timely informed of any new information pertaining to the 
study. 
13.5 
Archiving Study Records 
The essential study documents should be retained and archived until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. However, these documents should 
be retained for a longer period, if required by the applicable regulatory requirements or by an 

 
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agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/ 
institution as to when these documents no longer need to be retained. 

 
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14 
QUALITY ASSURANCE AND QUALITY CONTROL 
The Sponsor will implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted, and data are generated, documented, and reported in 
compliance with the protocol, ICH GCP E6 (R2), applicable regulatory requirements, and 
institutional research policies and procedures. 
14.1 
Monitoring 
The Investigator acknowledges that the monitor has the responsibility to review the clinical 
trial data for verification of proper recording and to verify the source data against the eCRF 
and to review the conduct of the clinical trial in compliance with the protocol and GCP. The 
Investigator will permit the site monitor to review study data as frequently as deemed 
necessary.  
 
The Investigator may not recruit patients into the study until such time that a visit has been 
made by a Sponsor monitor/representative, or with the agreement of the Sponsor/ formal 
training by Sponsor, to conduct a detailed review of the protocol and eCRF. 
 
The Investigator must cooperate with the Sponsor to ensure that the conduct of the clinical trial 
is GCP compliant. 
14.2 
Agreement and Compliance with the Protocol 
Prior to trial initiation, the protocol/ other related documents must be approved by the IEC/IRB/ 
regulatory authority in compliance with applicable regulatory requirements. Before the first 
patient is allowed to participate in the clinical trial, the Sponsor must ensure that all the ethical 
and legal requirements are met. 
 
The Investigator should not deviate from the protocol approved by the IRB/ IEC, except when 
the changes are necessary to eliminate a risk to the patients. This trial must accurately comply 
with the protocol. If changes to the protocol are required, the changes must be made in writing 
and notified or submitted for approval by the IRB/IEC/ regulatory authorities (as necessary). 
14.3 
Audits and Inspections 
An auditor from the Sponsor, the regulatory authorities, or the IEC/IRBs may conduct an audit 
or inspect the clinical sites. 
The purpose of audits and inspections is to systematically and independently verify that study-
related activities are performed, data in clinical studies are accurately recorded, analyzed and 
reported and that the study has been conducted in accordance with protocol, ICH- GCP E6 (R2) 
guidelines, and the applicable regulatory requirements. 
Regulatory authorities will communicate the purpose of the inspection to the Investigator and 
the Investigator should notify the Sponsor of the inspection. The Sponsor may provide support 
to the Investigator so that the site is inspection ready. 

 
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15 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
This study will be conducted in compliance with the protocol and with the ICH-GCP E6 (R2) 
guidelines for Technical Requirements for Registration of Pharmaceuticals for Human use, the 
World Medical Association Declaration of Helsinki (2013) and in compliance to the specific 
local regulatory requirements wherever applicable and required. 
15.1 
IEC/IRB Approval 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol, 
informed consent document and other applicable study documents have been reviewed and 
approved by an EC. The EC will be appropriately constituted and perform its functions in 
accordance with ICH- GCP E6 (R2) and local requirements as applicable. 
15.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each patient (or their legally 
acceptable representative). Before each patient is enrolled into the study, informed consent will 
be obtained from the patient (or his/her legally acceptable representative) according to the most 
current applicable regulatory and legal requirements. The consent will be obtained on the 
IEC/IRB approved and most recent version of consent form in language best comprehended by 
the patient. The consent documents to be used for the study will include all the elements of 
informed consent as outlined in the applicable regulatory guideline and should adhere to GCP 
and to the ethical principles that have their origin in the Declaration of Helsinki and be reviewed 
and approved by the appropriate EC prior to use at each site. 
 
The patients should be informed in a timely manner if new information becomes available that 
may be relevant to the patient’s willingness to continue participation in the trial. The patients 
will be re-consented as required. 
15.3 
Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without the prior written 
approval from the Sponsor. The anonymity of the participating patients must be maintained. 
Patients will be identified on the eCRF and other documents submitted to the Clinical Research 
Organization or the independent data management center by unique coded patient 
identification/ registration number but not by name. The confidentiality of records that could 
identify patients (e.g., the signed informed consent) should be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s) and 
should only be disclosed to the authorized study personnel/ Sponsor representative/ 
IEC/Regulatory authorities if required. 
 
15.4 
Liability and Insurance 
The Sponsor will obtain a reasonable third-party liability insurance coverage in accordance 
with all local legal regulatory requirements.  
The Sponsor will provide for insurance coverage with respect to liability caused by trial-related 
injuries caused by IPs being tested or by study-related procedures/ medical steps taken in the 
course of the study in accordance with the applicable regulatory requirement(s). The terms and 
conditions will apply as specified in the insurance policy document. 

 
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15.5 
Publication Policy 
The Sponsor shall retain the sole and exclusive ownership of any and all data arising (whether 
directly or indirectly) out of the conduct of clinical trials in relation to the Study (“Data”). Upon 
completion of the Study, the Sponsor may, at its sole discretion, arrange the analysis and 
tabulation of the Data. Sponsor shall be entitled to utilize the Data and clinical study report in 
any manner whatsoever including using the same for publication, presentation at scientific 
meetings or for submission with regulatory authorities in the manner it deems fit. Investigator 
hereby agrees and acknowledges that it shall not use and/or publish the data and/or any reports, 
presentation, information arising out of or in relation to the clinical trial without prior written 
approval of Lupin.  
 
Since such global studies are published with data of all patients pooled and analyzed together, 
isolated and independent publications at site/country level may provide inaccurate 
representation of safety, efficacy or immunogenicity of the investigational product. Hence, if 
the Investigators would like to publish/ present any paper/poster, the Investigators should 
provide Lupin the draft material to review for approval of any such proposed 
publication/presentation or other type of disclosure before it is submitted or disclosed in order 
to ensure against any inadvertent disclosure of confidential information or unprotected 
invention. For approval by Lupin, Investigator shall send such reports, presentation, 
information and/or data for Lupin’s review and approval at least 90 (ninety) days prior. It is 
hereby agreed that all proposed publications based on the Study shall be subject to the Sponsor's 
written approval with a possibility of denial for any reason including the reasons given above. 
If approved with comments from Lupin, Investigator shall incorporate all such comments 
suggested by the Sponsor in the publication. By signing this Protocol, Investigator agrees to 
unequivocally release the Data from the Study to the Sponsor without conditions and 
acknowledges this publication policy. 

 
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16 
APPENDICES 
 
16.1 
Appendix A: Preparation for Administration 
Details pertaining to preparation for administration of Investigational product is provided 
in Appendix A. 
 
 
16.2 
Appendix B: Study Management Details 
Study management/ study administrative details is provided in Appendix B. 
 
 
16.3 
Appendix C: Investigator’s Signature Page 
 
 
16.4 
Appendix D: Visual Functioning Questionnaire 
The NEI-VFQ-25 to be administered by interviewer at baseline, 3, 6, and 12 months is provided 
in Appendix D. 
 
 
 
 

 
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Version: 2.2; Dated 19 May 2022 
 
 
CONFIDENTIAL 
Page 60 of 61 
 
 
17 
REFERENCE LIST  
 
 
1 Hussain N; Khanna R; Hussain A. Trend of Retinal Diseases in Developing Countries, 
Expert Rev Ophthal Mol. 2008; 3(1):43-50 
2 WHO Website: Blindness and vision impairment prevention – Priority eye diseases. 
Url:https://www.who.int/blindness/causes/priority/en/index7.html; Accessed on 24 Apr 
2020 
3 Sobrin L, Seddon JM. Nature and nurture- genes and environment- predict onset and 
progression of macular degeneration. Prog Retin Eye Res. 2014;40:1–15 
4 Birch DG, Liang FQ. Age-related macular degeneration: a target for nanotechnology 
derived medicines. Int J Nanomedicine. 2007;2(1):65‐77. doi:10.2147/nano.2007.2.1.65 
5Lucentis 
EPAR 
Scientific 
Discussion, 
2007. 
Url: 
https://www.ema.europa.eu/en/documents/scientific-discussion/lucentis-epar-scientific-
discussion_en.pdf. Accessed on 24 Apr 2020 
6 The Angiogenesis Foundation. Advocating for Improved Treatment and Outcomes for 
Wet Age-Related Macular Degeneration, A Report Based on an International Expert 
Summit Convened in Berlin, Germany, November 2013. 
7 Wong WL, Su X, Li X, et. al. Global Prevalence Of Age-Related Macular Degeneration 
And Disease Burden Projection For 2020 And 2040: A Systematic Review And Meta-
Analysis. Lancet Glob Health 2014; 2: e106–16 
8 Khanani, AM, Skelly A, Bezlyak V et al. SIERRA-AMD: A Retrospective, Real-World 
Evidence Study of Patients with Neovascular Age-Related Macular Degeneration in the 
United States. Ophthalmology Retina. 2020; 4(2):122-133 
9 Fong AH, Lai TY. Long-term effectiveness of ranibizumab for age-related macular 
degeneration and diabetic macular edema. Clin Interv Aging. 2013;8:467‐483. 
doi:10.2147/CIA.S36811 
10 Lucentis® Summary of Product Characteristics (SmPC). Novartis Europharm Limited. 
Updated – Dec 2019. Url: https://www.medicines.org.uk/emc/product/307/smpc. Accessed 
on 18 Feb 2020 
11 Lucentis® Prescribing Information. Genentech, Inc. Updated - Mar 2018. Url: 
https://www.gene.com/download/pdf/lucentis_prescribing.pdf. Accessed on 18 Feb 2020 
12 Xu L, Lu T, Tuomi L et al. Pharmacokinetics of Ranibizumab in Patients with 
Neovascular Age-Related Macular Degeneration: A Population Approach. Investigative 
Ophthalmology & Visual Science March 2013, Vol.54, 1616-1624. 
13 Medical Review, Center for Drug Evaluation and Research, sBLA Number 
125156/053, Lucentis – Ranibizumab. 
http://www.accessdata.fda.gov/drugsatfda_docs/bla/2010/125156Orig1s053.pdf 
 
 

 
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14 David MB, Peter KK, et. al. Ranibizumab versus Verteporfin for Neovascular Age-
Related Macular Degeneration. N Engl J Med 2006;355:1432-44 
15 Philip JR, David MB, Jeffrey SH et. al. Ranibizumab for Neovascular Age-Related 
Macular Degeneration, N Engl J Med 2006;355:1419-31 
16 Busbee BG, Ho AC, Brown DM et. Al. Twelve-Month Efficacy and Safety of 0.5 mg 
or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-related Macular 
Degeneration. American Academy of Ophthalmology; 2013; 120:1046–1056 
17 American Academy of Ophthalmology Retina/ Vitreous Panel. Preferred Practice® 
Guidelines. Age Related Macular Degeneration. San Francisco, C.A: American Academy 
of Ophthalmology; 2015. Available at: www.aao.org/ppp. 

Appendix: C
Investigator's Signature Page Version: 
2.2; Dated 19 May 2022

NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
PB/IA 
National Eye Institute  
Visual Functioning Questionnaire - 25 
(VFQ-25) 
version 2000 
(INTERVIEWER ADMINISTERED FORMAT)
January 2000 
RAND hereby grants permission to use the "National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) 
July 1996, in accordance with the following conditions which shall be assumed by all to have been agreed to as a 
consequence of accepting and using this document: 
1. Changes to the NEI VFQ-25 - July 1996 may be made without the written permission of RAND.  However, all
such changes shall be clearly identified as having been made by the recipient. 
2. The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for the
accuracy of any translations of the NEI VFQ-25 Test Version - July 1996 into another language and for any errors, 
omissions, misinterpretations, or consequences thereof. 
3. The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for any
consequences resulting from the use of the NEI VFQ-25. 
4. The user of the NEI VFQ-25 - July 1996 will provide a credit line when printing and distributing this document
or in publications of results or analyses based on this instrument acknowledging that it was developed at RAND 
under the sponsorship of the National Eye Institute. 
5. No further written permission is needed for use of this NEI VFQ-25 - July 1996.
7/29/96 
© RAND 1996

- 1 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
Instructions: 
I’m going to read you some statements about problems which involve your vision 
or feelings that you have about your vision condition.  After each question I will 
read you a list of possible answers.  Please choose the response that best 
describes your situation. 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
Please take as much time as you need to answer each question.  All your 
answers are confidential.  In order for this survey to improve our knowledge 
about vision problems and how they affect your quality of life, your answers must 
be as accurate as possible.  Remember, if you wear glasses or contact lenses for 
a particular activity, please answer all of the following questions as though you 
were wearing them. 

- 2 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
Visual Functioning Questionnaire - 25 
PART 1 - GENERAL HEALTH AND VISION 
1.
In general, would you say your overall health is*:
(Circle One) 
READ CATEGORIES: 
Excellent ............................  1 
Very Good ..........................  2 
Good ..................................  3 
Fair .....................................  4 
Poor ....................................  5 
2.
At the present time, would you say your eyesight using both eyes
(with glasses or contact lenses, if you wear them) is excellent, good,
fair, poor, or very poor or are you completely blind?
(Circle One) 
READ CATEGORIES: 
Excellent ............................  1 
Good ..................................  2 
Fair .....................................  3 
Poor ....................................  4 
Very Poor ...........................  5 
Completely Blind ...............  6 
______________________ 
* Skip Question 1 when the VFQ-25 is administered at the same time as the SF-36 or RAND
36-Item Health Survey 1.0 

- 3 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
3.
How much of the time do you worry about your eyesight?
(Circle One) 
READ CATEGORIES: 
None of the time...........................  1 
A little of the time.........................  2 
Some of the time ..........................  3 
Most of the time ...........................  4 
All of the time? .............................  5 
4.
How much pain or discomfort have you had in and around your eyes
(for example, burning, itching, or aching)?  Would you say it is:
(Circle One) 
READ CATEGORIES: 
None ...................................  1 
Mild .....................................  2 
Moderate ............................  3 
Severe, or ..........................  4 
Very severe?......................  5 
PART 2 - DIFFICULTY WITH ACTIVITIES 
The next questions are about how much difficulty, if any, you have doing 
certain activities wearing your glasses or contact lenses if you use them for 
that activity. 
5.
How much difficulty do you have reading ordinary print in
newspapers?  Would you say you have:
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 

- 4 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
6.
How much difficulty do you have doing work or hobbies that require
you to see well up close, such as cooking, sewing, fixing things
around the house, or using hand tools? Would you say:
(READ CATEGORIES AS NEEDED)
 (Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
7.
Because of your eyesight, how much difficulty do you have finding
something on a crowded shelf?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
8.
How much difficulty do you have reading street signs or the names of
stores?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 

- 5 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
9.
Because of your eyesight, how much difficulty do you have going
down steps, stairs, or curbs in dim light or at night?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
10.
Because of your eyesight, how much difficulty do you have noticing
objects off to the side while you are walking along?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
11.
Because of your eyesight, how much difficulty do you have seeing
how people react to things you say?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 

- 6 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
12.
Because of your eyesight, how much difficulty do you have picking
out and matching your own clothes?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
13.
Because of your eyesight, how much difficulty do you have visiting
with people in their homes, at parties, or in restaurants?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 
14.
Because of your eyesight, how much difficulty do you have going out
to see movies, plays, or sports events?
(READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................................   1 
A little difficulty ......................................................   2 
Moderate difficulty .................................................   3 
Extreme difficulty ..................................................   4 
Stopped doing this because of your eyesight ....   5 
Stopped doing this for other reasons or not 
interested in doing this .........................................   6 

- 7 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
15.
Now, I’d like to ask about driving a car.  Are you currently driving, at
least once in a while?
(Circle One) 
Yes .....................  1 Skip To Q 15c 
No .......................  2 
15a. IF NO, ASK:  Have you never driven a car or have you given up 
driving? 
(Circle One) 
Never drove .......  1 Skip To Part 3, Q 17 
Gave up .............  2 
15b. IF GAVE UP DRIVING:  Was that mainly because of your 
eyesight, mainly for some other reason, or because of both your 
eyesight and other reasons? 
(Circle One) 
Mainly eyesight .................................  1 Skip To Part 3, Q 17 
Mainly other reasons ........................  2 Skip To Part 3, Q 17 
Both eyesight and other reasons ....  3 Skip To Part 3, Q 17 
15c. IF CURRENTLY DRIVING:  How much difficulty do you have 
driving during the daytime in familiar places?  Would you say 
you have: 
(Circle One) 
No difficulty at all ..............................  1 
A little difficulty .................................  2 
Moderate difficulty ............................  3 
Extreme difficulty ..............................  4 

- 8 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
16.
How much difficulty do you have driving at night?  Would you say you
have: (READ CATEGORIES AS NEEDED)
(Circle One) 
No difficulty at all ...................................  1 
A little difficulty ......................................  2 
Moderate difficulty .................................  3 
Extreme difficulty ...................................  4 
Have you stopped doing this because 
of your eyesight .....................................  5 
Have you stopped doing this for other 
reasons or are you not interested in  
doing this ................................................  6 
16a. How much difficulty do you have driving in difficult conditions, such 
as in bad weather, during rush hour, on the freeway, or in city traffic?  
Would you say you have: 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
No difficulty at all ...................................  1 
A little difficulty ......................................  2 
Moderate difficulty .................................  3 
Extreme difficulty ...................................  4 
Have you stopped doing this because 
of your eyesight .....................................  5 
Have you stopped doing this for other 
reasons or are you not interested in  
doing this ................................................  6 

- 9 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
PART 3:  RESPONSES TO VISION PROBLEMS 
The next questions are about how things you do may be affected by your 
vision. For each one, I’d like you to tell me if this is true for you all, most, 
some, a little, or none of the time. 
(Circle One On Each Line) 
READ CATEGORIES: 
All of 
the 
time 
Most of 
the 
time 
Some 
of the 
time 
A little 
of the 
time 
None of 
the 
time 
17. Do you accomplish
less than you would
like because of your
vision? ............................ 
1 
2 
3 
4 
5 
18. Are you limited in how
long you can work or do
other activities because
of your vision? ............... 
1 
2 
3 
4 
5 
19. How much does pain or
discomfort in or around
your eyes, for example,
burning, itching, or
aching, keep you from
doing what you’d like to
be doing?  Would you
say: ................................. 
1 
2 
3 
4 
5 

- 10 - 
version 2000 
© RAND 1996
NEI-VFQ25-IA - United States/English – Original version. 
NEI-VFQ25-IA_AU1.0_eng-USori.doc
For each of the following statements, please tell me if it is definitely true, 
mostly true, mostly false, or definitely false for you or you are not sure. 
(Circle One On Each Line) 
Definitely 
True 
Mostly 
True 
Not 
Sure 
Mostly 
False 
Definitely 
False 
20. I stay home most of the time
because of my eyesight ........ 
1 
2 
3 
4 
5 
21. I feel frustrated a lot of the
time because of my
eyesight ................................ 
1 
2 
3 
4 
5 
22. I have much less control
over what I do, because of
my eyesight .......................... 
1 
2 
3 
4 
5 
23. Because of my eyesight, I
have to rely too much on
what other people tell me .... 
1 
2 
3 
4 
5 
24. I need a lot of help from
others because of my
eyesight ................................ 
1 
2 
3 
4 
5 
25. I worry about doing things
that will embarrass myself
or others, because of my
eyesight ................................ 
1 
2 
3 
4 
5 
That’s the end of the interview.  Thank you very much for your time and 
your help.