A Phase III Double-Blind, Parallel Group, Multicenter Study to Compare the Efficacy and Safety of Xlucane Versus Lucentis® in Patients With Neovascular Age-Related Macular Degeneration
Phase: PHASE3
Conditions: Macular Degeneration
Sponsor: Xbrane Biopharma AB

 
 
CLINICAL STUDY PROTOCOL 
 
Xplore: A Phase III Double-Blind, Parallel Group, Multicenter Study to 
Compare the Efficacy and Safety of Xlucane versus Lucentis® in Patients 
with Neovascular Age-Related Macular Degeneration 
 
Protocol Number: 
XBR1001 
EudraCT Number: 
2018-002930-19 
Syneos Health Study Number: 1009980 
Investigational Product: 
Xlucane  
Phase: 
III 
Sponsor: 
Xbrane Biopharma 
Retzius väg 8   
SE-171 65 Solna  
Sweden 
Contract Research 
Organization: 
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
United States 
Protocol Date: 
24 Feb 2021 
Protocol Version: 
Amendment 5, Version 1.0 
 
 
CONFIDENTIAL 
This Clinical Study Protocol contains privileged or confidential information which is 
the property of Xbrane Biopharma (the Sponsor) and may not be used, divulged, 
published, or otherwise disclosed without written authorisation from the Sponsor.  
Restrictions on disclosure will apply equally to all future information supplied to you or 
generated by you relating to the study. 

 
Xbrane Biopharma                                                                                                                                 24 Feb 2021 
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1 
PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
Xplore: A Phase III Double-Blind, Parallel Group, Multicenter 
Study to Compare the Efficacy and Safety of Xlucane versus 
Lucentis® in Patients with Neovascular Age-Related Macular 
Degeneration 
 
EudraCT Number: 2018-002930-19 
Protocol Number: 
XBR1001 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for current Good Clinical Practice 
(GCP) and applicable regulatory requirements. 

 
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2 
STUDY PERSONNEL 
Sponsor Personnel 
Name: 
Dina Jurman 
Title: 
Head of Clinical Affairs 
Address: 
Xbrane Biopharma AB 
Retzius väg 8   
SE-171 65 Solna, Sweden 
Mobile: 
+46 702 668 458 
 
CRO Personnel 
Project Manager: 
Phillipa Hughes 
Senior Project Manager, Ophthalmology 
Syneos Health 
  
Direct +44 (0)1926 857534   
Mobile +44 (0)7766 511860 
Clinical Lead: 
Daria Fotunyants, MD  
Clinical Monitoring Project Lead, CNS, Clinical Solutions 
inVentiv Health Clinical LLC – a Syneos Health company 
Syneos Health 
Direct  +7 812 676 7240 (ext. 67130)  
Mobile +7 911 777 6398  
Other Personnel 
Medical Monitor, Europe: 
Anna Dudzik, MD 
Executive Medical Director 
Medical Management and Scientific Services 
Clinical Solutions 
Syneos Health 
Direct: +4 812 646 2516 
Mobile: + 4 860 447 1518 
 

 
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Medical Monitor, North America: 
Peter Nicholas, MD, PhD 
Medical Director 
Medical Management and Scientific Services 
Clinical Solutions 
Syneos Health 
Direct: +1 919 926 5639 
Mobile: +1 919 259 9521 
 
Medical Monitor, Asia-Pacific: 
Mugdha Tapdiya 
Associate Medical Director  
Medical Management and Scientific Services 
Clinical Solutions 
Syneos Health 
Direct: +9 1 114 057 0845 
Mobile: +9 1 882 680 4161 
Email: mugdha.tapdiya@syneoshealth.com 
 
Biostatistician 
Gary Smith 
Principal Biostatistician 
Syneos Health 
Direct: +44 127 648 1578 
Email: gary.smith3@syneoshealth.com 
Central Laboratory, Europe (and Asia) 
Company Name: Q2 Solutions – Central Laboratories 
Address: 
The Alba Campus  
Rosebank 
Livingston 
West Lothian, EH54 7EG 
Scotland, UK 
Telephone No.: + 44 (0) 1506 81 4000 
Fax No.: 
+ 44 (0) 1506 81 4199 
*The Central Laboratory in North America (listed below) may be used in case of disruptions/delays 
associated the planned exit of UK from the European Union. 

 
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Central Laboratory, North America 
Company Name: Q2 Solutions – Central Laboratories 
Address: 
27027 Tourney Road, Suite 2E  
Valencia, CA 91355 
USA 
Telephone No.: +1 661 799 6550 
Fax No.:  
+1 661 799 5263 
Central Reading Center 
Company Name: Association for Innovation and Biomedical Research on Light and 
Image (AIBILI) 
Coimbra Ophthalmology Reading Center (CORC) 
Address: 
Azinhaga de Santa Comba, Celas 
3000-548 Coimbra 
Portugal 
Telephone No.: +35 123 948 0149 
Immunogenicity/Pharmacokinetics Laboratory 
Company Name: inVentiv Clinical Lab, a Syneos Health company 
Address: 
301D College Road East 
Princeton, NJ 08540 
USA 
Telephone No.: +1 609 951 0005 
 

 
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3 
SYNOPSIS 
Protocol Number: 
XBR1001 
Title: 
Xplore: A Phase III Double-Blind, Parallel Group, Multicenter Study to Compare the 
Efficacy and Safety of Xlucane versus Lucentis® in Patients with Neovascular Age-
Related Macular Degeneration 
Investigational Product: 
Xlucane  
Study Centers: 
This study will be conducted at approximately 160 sites in approximately 15 countries 
in the United States, Europe, the Middle East, and Asia-Pacific. 
Phase: 
Phase III 
Objectives: 
Primary objective:  
The primary objective of the study is to demonstrate that the proposed biosimilar 
candidate Xlucane is equivalent to Lucentis® in subjects with wet (ie, neovascular) age-
related macular degeneration (wAMD) as assessed by the change in best corrected visual 
acuity (BCVA) from Baseline to Week 8. 
Secondary objectives: 
• Evaluate the efficacy of Xlucane vs Lucentis® in subjects with wAMD based on 
central foveal thickness measured by spectral domain optical coherence tomography 
(SD-OCT), area of choroidal neovascularization, and presence of leakage assessed by 
fundus fluorescein angiography (FA) 
• Evaluate the safety of Xlucane vs Lucentis® 
• Evaluate the systemic exposure of Xlucane vs Lucentis® in subjects participating in 
pharmacokinetics (PK) evaluation 
• Evaluate immunogenicity (ie, anti-ranibizumab antibodies and neutralizing anti-drug 
antibodies [NAb]) of Xlucane vs Lucentis® 
Study Design: 
This is a phase III multicenter, double-blind (double-masked), randomized, parallel group 
study in subjects with wAMD. Approximately 580 subjects will be enrolled and 
randomized in a 1:1 ratio to receive either Lucentis® (0.05 mL of 10 mg/mL ranibizumab) 
or the investigational product, Xlucane (0.05 mL of 10 mg/mL ranibizumab), in the study 
eye once every 4 weeks (monthly) for 52 weeks (ie, 12 months).  

 
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The study eye will be defined as the eye meeting all of the inclusion criteria and none of 
the exclusion criteria (ie, the enrollment criteria).  
The assigned study drug will be administered as an ophthalmic intravitreal (IVT) 
injection. Designated, unmasked study staff will prepare and administer the study drug, 
ensuring that the masking of the subject is maintained during the injection procedure.  
Subjects will be randomized by interactive web response system (IWRS) to receive 
13 doses of either Xlucane or Lucentis® in the study eye. The randomization scheme will 
automatically ensure that the study drug assignment for a given subject is random and 
that an overall 1:1 ratio of assignments to each of the 2 study drug treatments is 
approximated. In addition, the randomization scheme will include the following 
stratification parameters to ensure balanced distribution of assignment to the 2 treatments: 
eye color (light iris vs dark iris), geographical region where enrolled and the BCVA letters 
at Baseline (55 or lower, 56 to 65, 66 or higher). Subjects will be followed up for changes 
in efficacy variables and safety for 52 weeks. Each subject’s involvement will last up to 
approximately 52 weeks (ie, 12 months). 
At the beginning of the study, a subgroup of 60 subjects at a select number of participating 
sites will be sequentially asked to participate in an evaluation of PK. This subgroup will 
be asked to provide blood samples for measurement of plasma ranibizumab immediately 
before administration of the first dose of Xlucane or Lucentis®. Additional samples will 
be collected at 23 hours (± 60 minutes) after the first dose (ie, Day 1) and at 23 hours (± 
60 minutes) after the sixth dose (ie, Week 20) at expected time to maximum plasma 
concentration (Tmax, which is around 22 hours).  
An interim analysis will be performed on unmasked study data. After all of the 
randomized subjects have 6-month (ie, 24 weeks) data available, an unmasked analysis 
of efficacy and safety endpoints as well as PK and immunogenicity will be performed. 
The aim of the unmasked analysis is to initiate the submission of the application for 
marketing authorization as agreed with the European Medicines Agency. 
This analysis will not affect the further conduct of the study. The site staff personnel will 
not receive details of patients’ individual treatment assignment  and therefore the blinding 
of patients' individual treatment and thereby the study will be maintained until completion 
of the study.  
FA, CFP, and OCT will be performed at Screening. The images will be sent to the central 
reading center (CRC) for interpretation and confirmation of eligibility. The CRC will also 
grade images that are collected during the study.  
 
 
 
 
 
 

 
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Study Design 
 
Number of Subjects:  
It is anticipated that approximately 580 subjects will be enrolled and randomized.  
Treatment: 
Subjects will be randomized in a 1:1 ratio to receive Lucentis® (0.05 mL of 10 mg/mL 
ranibizumab), or the proposed biosimilar, Xlucane (0.05 mL of 10 mg/mL 
ranibizumab), once every 4 weeks (intravitreal injection) for 52 weeks (12 months).  
Subjects will be randomized on Day 0. Only 1 eye (ie, the study eye) per subject will 
receive Xlucane or Lucentis®. Subjects will visit the site for study assessments after the 
first dose at Week 2 and every 4 weeks thereafter, for a total of 52 weeks. (Subjects 
participating in the PK sub-study will need to visit the site more often [ie, at least two 
more times].) Week 52 will be the End of Treatment visit. 
Study Duration: 
Each subject’s involvement will last approximately 52 weeks (ie, 12 months), including 
follow-up. 
Study Population: 
Inclusion criteria 
To be eligible for study entry, subjects must satisfy all of the following inclusion 
criteria: 
1. Written and signed informed consent form obtained at screening before any study-
related procedures are performed. Patients must be capable of providing their own 
consent (an impartial witness must be present in case of illiterate patients). 
2. Willingness and ability to undertake all scheduled visits and assessments as judged 
by the investigator. 
3. Newly diagnosed, active subfoveal choroidal neovascularization (CNV) lesion 
secondary to age-related macular degeneration (AMD) in the study eye. Note: active 
CNV indicates the presence of leakage as evidenced by fluorescein angiography (FA) 

 
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and intra- or subretinal fluid as evidenced by optical coherence tomography (OCT), 
which must be confirmed by the central reading center during Screening: 
a. The area of CNV must be ≥ 50% of the total lesion area in the study eye, and  
b. Total lesion area ≤ 9.0 disc areas (DA) in size (including blood, scars, and 
neovascularization) as assessed by FA in the study eye.  
4. BCVA of ≤ 73 and ≥ 49 Early Treatment Diabetic Retinopathy Study (ETDRS) letter 
score in the study eye using the ETDRS chart (20/40 to 20/100 Snellen equivalent) at 
Screening. 
5. Fellow eye should not be expected to need any anti-vascular endothelial growth 
factor (VEGF) treatment for the duration of study participation based on 
Investigator’s decision. 
6. Age ≥ 50 years at screening. 
7. Male and female subjects of childbearing potential must be willing to completely 
abstain or agree to use an appropriate method of contraception from the time of 
signing informed consent form and for the duration of study participation through 
3 months after the last dose of study drug. See Appendix 17.1 for examples of 
acceptable contraception. (The investigator and each subject will determine the 
appropriate method of contraception for the subject during the participation in the 
study.) 
a. A woman of childbearing potential is any woman, regardless of sexual 
orientation, who meets the following criteria: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 12 consecutive months (ie, has had menses at any 
time in the preceding 12 consecutive months). 
b. A man of sexual potential is any man who has not been surgically sterilized 
(eg, has not undergone bilateral orchiectomy). 
Exclusion criteria 
Subjects will be excluded from the study if 1 or more of the following exclusion 
criteria is applicable:  
1. Any previous intervention, including pharmacological treatment, laser, and/or surgery 
for wAMD in either eye; (Exception: Vitamin supplementation for AMD prevention). 
(In case of end stage wAMD in fellow eye where anatomical and functional status 
diagnosed on Screening, disqualifies subject from intravitreal anti-VEGF treatment 
according to local medical standards of care, the previous laser photocoagulation or 
PDT procedure in fellow eye performed for wAMD treatment is allowed). (This 
criterion is not applicable for fellow eye, in case of subjects who have only one eye 
or the fellow eye fulfills additional criteria specified in  Section 8.3.4). 
2. Any previous vitreoretinal surgery in the study eye for any cause. 
3. Any previous IVT treatment, including any anti-VEGF medications, steroids, and/or 
any other investigational medication in either eye. 

 
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4. The use of long-acting steroids, either systemic or intraocular in any eye, in the 
18 months before planned initiation of study treatment. (Note: Current or planned 
Iluvien® [fluocinolone acetonide intravitreal] implantation during the study is 
prohibited.) 
5. Subfoveal fibrosis, subfoveal atrophy, and/or scarring extending > 50% of total lesion 
area in the study eye as assessed by the investigator at screening and confirmed by 
the central reading center prior to Randomization. 
6. Choroidal neovascularization in either eye due to non-AMD causes (eg, diabetic 
macular edema, retinal vein occlusion, ocular histoplasmosis, trauma) as assessed by 
FA and confirmed by central reading center. (This criterion is not applicable for 
fellow eye, in case of subjects who have only one eye or the fellow eye optical media 
opacity prevents from taking the FA/OCT/FP images and the fellow eye fulfills 
additional criteria specified in  Section 8.3.4). 
7. Active or recent (within 28 days prior to Randomization) intraocular, extraocular, and 
periocular inflammation or infection in either eye. 
8. History of idiopathic or autoimmune-associated uveitis in either eye. 
9. Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
10. Unmedicated intraocular pressure (IOP) ≥ 30 mm Hg at Screening in either eye. 
11. Topical ocular corticosteroids administered for ≥ 30 consecutive days in the study eye 
within 90 days prior to Screening. 
12. Spherical equivalent of the refractive error in the study eye demonstrating more than 
8 diopters of myopia. 
13. Corneal transplant or corneal dystrophy in the study eye. 
14. History of rhegmatogenous retinal detachment in the study eye. 
15. History of macular hole in the study eye. 
16. Retinal pigment epithelial tear or rip involving the macula in the study eye as assessed 
by FA and confirmed by the central reading center. 
17. Current vitreous hemorrhage in the study eye. 
18. Subretinal hemorrhage that is ≥ 50% of the total lesion area in the study eye, or if the 
subretinal hemorrhage involves the fovea is 1 or more DA (≥ 2.54 mm2) in size in the 
study eye, as assessed by FA and confirmed by the central reading center. 
19. Other intraocular surgery (including cataract surgery) in the study eye within the 
3 months prior to Baseline. The yttrium aluminum garnet [YAG] posterior 
capsulotomy is allowed no later than 4 weeks prior to screening. 
20. Any concurrent intraocular condition in the study eye (eg, cataract or diabetic 
retinopathy) that, in the opinion of the investigator, could require treatment during the 
study period to prevent or treat loss of visual acuity. 
21. Significant media opacities (including cataract) in the study eye interfering with 
BCVA assessment or fundus imaging (FA/fundus photography/OCT). 

 
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22. Aphakia or absence of the posterior capsule in the study eye, unless it occurred as a 
result of a YAG posterior capsulotomy in association with prior posterior chamber 
intraocular lens implantation. 
23. Presence of advanced glaucoma or optic neuropathy that involves or threatens the 
central visual field in the study eye (as judged by the investigator). 
24. History of glaucoma filtering surgery or argon laser trabeculoplasty in the study eye 
(Exception: Laser iridotomy and selective laser trabeculoplasty are allowed).  
25. Uncontrolled ocular glaucoma or hypertension in the study eye, defined as IOP ≥ 25 
mm Hg despite treatment with anti-glaucoma medication.  
26. Any previous systemic anti-VEGF treatment (eg, bevacizumab). 
27. Contraindication for Lucentis® (hypersensitivity to ranibizumab or to any of the study 
treatment excipients). 
28. Current treatment for active systemic infection. 
29. Females who are pregnant, nursing, planning a pregnancy during the study, or of 
childbearing potential and not using a reliable method of contraception (see Appendix 
17.1) and/or not willing to use a reliable method of contraception during their 
participation in the study. A pregnancy test administered to women of childbearing 
potential at the Screening Visit (prior to treatment) must be negative for the patient to 
receive study medication. 
30. Participation in another clinical trial within the previous 3 months or any other clinical 
trial of anti-angiogenic drugs. 
31. Reasonable suspicion of other disease or condition that might render the subject at a 
high risk of treatment complications or otherwise confound interpretation of the study 
results (as judged by the investigator). 
32. PK subgroup only: Contraindication for additional blood sampling (as judged by the 
investigator). 
Primary Efficacy Endpoint: 
• Change in BCVA letters at Week 8 compared to Baseline using the ETDRS 
protocol. 
Secondary Efficacy Endpoints: 
• Change in BCVA letters at Week 4, Week 12, Week 16, Week 24, Week 36 and Week 
52 compared to Baseline using the ETDRS protocol 
• Change in total size of choroidal neovascular leakage area in the study eye measured 
by FA at Week 24 and Week 52 compared to Baseline 
• Change in total size of choroidal neovascularization in the study eye measured by FA 
at Week 24 and Week 52 compared to Baseline 

 
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• Change in Central Foveal Thickness (CFT) in the study eye measured by OCT at 
Week 2, Week 4, Week 8, Week 16, Week 24, Week 36 and Week 52 compared to 
Baseline 
• Changes in the size and/or number of intraretinal cystoid space (cysts), subretinal 
fluid, and retinal pigment epithelium detachments in the study eye measured by 
qualitative morphology-based OCT 
• Percentage of subjects with loss of < 15 letters using ETDRS, evaluated as change at 
Week 4, Week 8, Week 24, and Week 52 compared to Baseline in the study eye 
• Percentage of subjects with a gain of ≥ 15 letters using ETDRS, evaluated as change 
at Week 4, Week 8, Week 24, and Week 52 compared to Baseline in the study eye 
• Percentage of subjects without intra- or subretinal fluid in the study eye (ie, 
completely dry) at Week 24 and Week 52 
• Percentage of subjects with retinal pigment epithelium detachments in the study eye 
• Systemic ranibizumab concentrations 
Safety Endpoint(s): 
• Adverse events (AEs), including treatment-emergent adverse events (TEAEs) and 
serious adverse events (SAEs) 
• Injection site reactions (including endophthalmitis, vitritis, and hemorrhage) 
• Immunogenicity (ie, anti-ranibizumab antibodies and NAb)  
• Hematology and clinical chemistry (including analysis of alanine aminotransferase 
also known as serum glutamic-pyruvic transaminase [ALT/SGPT] and aspartate 
aminotransferase also known as serum glutamic-oxaloacetic transaminase 
[AST/SGOT], and creatinine) 
Statistical Analysis: 
For the primary estimand, the scientific question of interest is the between-group 
difference (Xlucane v Lucentis®) in the mean change from baseline in BCVA letter score 
at Week 8 in patients who fulfil the study eligibility criteria, have no Intercurrent Events 
up to and including the Week 8 BCVA assessment and complete 8 weeks of treatment of 
study drug (given as a single ophthalmic IVT injection every 4 weeks/monthly). 
Before unmasking the data for subjects included in this trial, a statistical analysis plan 
(SAP), which will provide the technical details of the statistical analyses outlined here, 
will be prepared, finalized, and signed. In general, data will be summarized by means of 
summary statistics. Continuous data will be presented as the number of observations, 
mean, standard deviation (SD), minimum, Q1, median, Q3, and maximum. Categorical 
data will be presented as counts and percentages. The data will be presented for each 
treatment group by visit. 
Efficacy data (ROW): Biosimilarity will be concluded if the two-sided 95% confidence 
interval (CI) for the difference in mean change in BCVA at Week 8 between the Xlucane 
and Lucentis® is confined within the equivalence margin of ± 3.5 letters. 

 
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Efficacy data (US FDA): Biosimilarity will be concluded if the two-sided 90% confidence 
interval (CI) for the difference in mean change in BCVA at Week 8 between the Xlucane 
and Lucentis® is confined within the equivalence margin of ± 3.5 letters. 
The difference in the approach around the confidence interval is based on the regulatory 
requirement in the United States (90% CI) and the rest of the world (95% CI), as agreed 
with the relevant regulatory authorities. 
The change in BCVA letters at Week 8 compared to Baseline using the ETDRS protocol 
will be analyzed using a mixed model for repeated measures (MMRM). An MMRM 
approach will be fitted with geographical region of the country where enrolled, visit, eye 
color (light iris vs dark iris), treatment, and treatment-by-visit interaction as fixed effects, 
with the Baseline BCVA letters and Baseline BCVA letters-by-visit interaction as 
covariates. The treatment differences from the model at Week 8 will be evaluated and a 
95% or 90% two-sided CI for the least squares mean difference between groups will be 
calculated. To prove the 2 products to be biosimilar, the confidence limits for this 
difference have to be within the equivalence margin of ±3.5 letters.  The primary analysis 
for assessment of biosimilarity will be based on the primary estimand. 
Interim analysis: When all subjects have completed their 6-month assessments, an 
unmasked analysis of efficacy and safety endpoints as well as PK and immunogenicity 
will be performed.  The aim of the unmasked analysis is to initiate the submission of the 
application for marketing authorization as agreed with the European Medicines Agency. 
This analysis will not affect the further conduct of the study.  
PK data: The PK data (plasma levels of ranibizumab) will be compared between 2 groups 
of subjects receiving Xlucane and Lucentis® in a statistical non-confirmatory manner, for 
comparative purpose.  
Safety data: AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be tabulated by system organ class (SOC) and preferred term (PT). 
The total number of subjects with at least one TEAE and the total number of TEAEs will 
be presented. Number of subjects and number of TEAEs will be tabulated by SOC and 
PT. TEAEs will also be tabulated according to worst severity and relationship to 
treatment. 
Sample Size: The sample size calculation was based on the primary efficacy endpoint: 
Change in BCVA between Baseline and Week 8. 
A 95% or 90% two-sided CI for the difference between groups will be calculated. The 
difference in the approach around the confidence interval is based on the regulatory 
requirement in the United States (90% CI) and the rest of the world (95% CI), as agreed 
with the relevant regulatory authorities. To prove the 2 products to be biosimilar, the 
confidence limits for this difference have to be within the equivalence margin of ±3.5 
letters. 
For the purpose of sample size calculation, an SD of 10 letters will be assumed for this 
study. This is based on an analysis of the data from clinical trials of the originator product 
demonstrating a clear correlation between baseline BCVA and the SD of the change of 
BCVA at Week 8. Considering that a narrower inclusion criterion for BCVA is being 

 
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applied in this study compared to the studies of the originator product, it is expected that 
a baseline BCVA of around 60 letters will be observed. Therefore, an SD of 10 for the 
primary endpoint is well in the upper range of what is expected. 
From 580 randomized patients there will be >90% power to show equivalence (ie, two-
sided 95% CI for the mean difference between Xlucane and Lucentis® is confined within 
the equivalence margin of ± 3.5 letters) if the SD is no more than 10. 

 
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4 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures ......................................................................... 2 
2 
Study Personnel ................................................................................................ 3 
3 
Synopsis ............................................................................................................. 6 
4 
Table of Contents............................................................................................ 15 
5 
List of Abbreviations ...................................................................................... 19 
6 
Introduction .................................................................................................... 22 
6.1 
Background: Disease ...................................................................................... 22 
6.2 
Xlucane ............................................................................................................ 23 
6.2.1 
Quality Development ...................................................................... 24 
6.2.2 
Summary of Nonclinical Development ........................................... 24 
6.2.2.1 
Primary and Higher Order Structures .............................................. 25 
6.2.2.2 
Purity/Impurity Profile .................................................................... 25 
6.2.2.3 
Potency and Binding ....................................................................... 26 
6.2.2.4 
Pharmacokinetic Study in Rabbits .................................................. 26 
6.2.3 
Planned Clinical Study .................................................................... 28 
6.3 
Lucentis® (ranibizumab injection) ................................................................ 28 
6.3.1 
Nonclinical Studies.......................................................................... 29 
6.3.1.1 
Infertility .......................................................................................... 29 
6.3.2 
Clinical Studies in wAMD .............................................................. 29 
7 
Study Objectives ............................................................................................. 31 
7.1 
Primary Objective .......................................................................................... 31 
7.2 
Secondary Objectives ..................................................................................... 31 
8 
Investigational Plan ........................................................................................ 32 
8.1 
Overall Study Design and Plan: Description ............................................... 32 
8.1.1 
Schedule of Assessments................................................................. 34 
8.1.2 
Schedule of Additional Assessments for PK Subgroup 
ONLY .............................................................................................. 38 
8.2 
Discussion of Study Design ............................................................................ 39 
8.2.1 
Study Design ................................................................................... 39 
8.3 
Selection of Study Population ........................................................................ 41 
8.3.1 
Number of Planned Subjects ........................................................... 41 
8.3.2 
Inclusion Criteria ............................................................................. 41 

 
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8.3.3 
Exclusion Criteria ............................................................................ 42 
8.3.4 
Optic media opacity in one eye (fellow eye) ................................... 45 
8.3.5 
Removal of Subjects From Therapy or Assessments ...................... 45 
8.4 
Study Medications .......................................................................................... 46 
8.4.1 
Identity of Study Medication ........................................................... 47 
8.4.1.1 
Xlucane ............................................................................................ 47 
8.4.1.2 
Lucentis® (ranibizumab injection)................................................... 48 
8.4.2 
Packaging and Labeling .................................................................. 48 
8.4.3 
Randomization................................................................................. 50 
8.4.4 
Selection of Doses in the Study ....................................................... 50 
8.4.5 
Selection and Timing of Dose for Each Subject ............................. 50 
8.4.6 
Masking ........................................................................................... 51 
8.4.7 
Prior and Concomitant Therapy ...................................................... 52 
8.4.7.1 
Rescue Medication .......................................................................... 53 
8.4.8 
Known Contraindications ................................................................ 53 
8.4.8.1 
Ocular or Periocular Infections ....................................................... 53 
8.4.8.2 
Hypersensitivity............................................................................... 53 
8.4.9 
Warnings and Precautions ............................................................... 53 
8.4.9.1 
Endophthalmitis and Retinal Detachments ..................................... 53 
8.4.9.2 
Increases in Intraocular Pressure ..................................................... 54 
8.4.9.3 
Thromboembolic Events ................................................................. 54 
8.4.10 
Treatment Compliance .................................................................... 54 
9 
Timing of Study Procedures .......................................................................... 54 
9.1 
Pre-treatment .................................................................................................. 55 
9.1.1 
Screening Visit (Visit 1) .................................................................. 55 
9.2 
Treatment Period ........................................................................................... 56 
9.2.1 
Day 0 Visit (Visit 2) - Baseline ....................................................... 56 
9.2.1.1 
Day 1 (Visit 2b) for PK subgroup ONLY ....................................... 57 
9.2.2 
Week 2/ Visit 3 (± 2 days) ............................................................... 57 
9.2.3 
Week 4/ Visit 4 (± 2 days) ............................................................... 58 
9.2.4 
Week 8/ Visit 5 (± 2 days) ............................................................... 58 
9.2.5 
Week 12/ Visit 6 (± 5 days) ............................................................. 59 
9.2.6 
Week 16/ Visit 7 (± 5 days) ............................................................. 60 
9.2.7 
Week 20/ Visit 8 (± 5 days) ............................................................. 60 
9.2.7.1 
Week 20 (Visit 8b) for PK subgroup ONLY .................................. 61 
9.2.8 
Week 24/ Visit 9 (± 5 days) ............................................................. 61 
9.2.9 
Week 28 to Week 48 (every 28 days or every 4 weeks; 
monthly) [Visits 10 to 15] (± 5 days) .............................................. 62 
9.2.10 
Week 52/ End-of-treatment or Early Withdrawal Visit/ 
Visit 16 (± 5 days) ........................................................................... 63 
9.3 
Duration of Treatment ................................................................................... 64 

 
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10 
Efficacy, Pharmacokinetics, ImmunogenicITY, and Safety 
Variables.......................................................................................................... 64 
10.1 Efficacy, Pharmacokinetics, Immunogenicity, and Safety 
Measurements Assessed ................................................................................. 64 
10.1.1 
Efficacy Variables ........................................................................... 64 
10.1.1.1 Best Corrected Visual Acuity Assessment ...................................... 64 
10.1.1.2 Central Foveal Thickness ................................................................ 64 
10.1.1.3 Morphological Changes in the Neovascular Membrane ................. 64 
10.1.1.4 Choroidal Neovascularization ......................................................... 64 
10.1.2 
Pharmacokinetic Variables .............................................................. 65 
10.1.2.1 Pharmacokinetic Assessment(s) ...................................................... 65 
10.1.3 
Immunogenicity Variables .............................................................. 65 
10.1.4 
Safety Variables .............................................................................. 65 
10.1.4.1 Safety Assessments ......................................................................... 65 
10.1.4.2 Adverse Events ................................................................................ 65 
10.1.5 
Appropriateness of Measurements .................................................. 71 
10.1.6 
Drug Concentration Measurements ................................................. 71 
10.2 Stopping Rules ................................................................................................ 71 
11 
Statistical Methods ......................................................................................... 72 
11.1 General Considerations ................................................................................. 72 
11.2 Analysis Sets .................................................................................................... 72 
11.3 Planned Analyses ............................................................................................ 73 
11.3.1 
Patient Disposition .......................................................................... 73 
11.3.2 
Demographic and Other Baseline Characteristics ........................... 73 
11.3.3 
Efficacy Endpoints .......................................................................... 73 
11.3.3.1 Primary Efficacy Endpoint .............................................................. 73 
11.3.3.2 Secondary Efficacy Endpoints ........................................................ 74 
11.3.4 
Safety Endpoints.............................................................................. 75 
11.3.4.1 Adverse Events ................................................................................ 75 
11.3.4.2 Other Safety Endpoints ................................................................... 76 
11.3.5 
Pharmacokinetics............................................................................. 76 
11.3.6 
Interim Analyses.............................................................................. 76 
11.3.7 
Handling of Missing Data ............................................................... 76 
11.4 Determination of Sample Size ....................................................................... 77 
11.5 Protocol Deviations......................................................................................... 78 
12 
Quality Assurance and Quality Control ....................................................... 78 
12.1 Audit and Inspection ...................................................................................... 78 
12.2 Monitoring ...................................................................................................... 78 

 
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12.3 Data Management and Coding ..................................................................... 78 
12.4 Quality Management and Risk Evaluation .................................................. 79 
13 
Records and Supplies ..................................................................................... 80 
13.1 Drug Accountability ....................................................................................... 80 
13.2 Financing and Insurance ............................................................................... 80 
14 
Ethics ............................................................................................................... 81 
14.1 Independent Ethics Committee or Institutional Review Board ................. 81 
14.2 Regulatory Authorities................................................................................... 81 
14.3 Ethical Conduct of the Study ........................................................................ 81 
14.4 Informed Consent ........................................................................................... 81 
14.5 Subject Confidentiality .................................................................................. 82 
15 
Reporting and Publication, Including Archiving ........................................ 83 
16 
References ....................................................................................................... 84 
17 
Appendices ...................................................................................................... 86 
17.1 Examples of Acceptable Contraception ....................................................... 86 
17.2 Investigator Signature Page .......................................................................... 87 
18 
Protocol Amendment Summary of Changes................................................ 88 
18.1 Summary of Changes ..................................................................................... 88 
 
TABLE OF TABLES 
Table 1: Experimental Design of Rabbit PK Study ........................................................ 27 
Table 2 Meta-analysis wAMD Ranibizumab Studies using BCVA change at 8 weeks 40 
Table 3 Study Medication Details .................................................................................. 47 
 
TABLE OF FIGURES 
Figure 1 Study Design .................................................................................................... 33 
 

 
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5 
LIST OF ABBREVIATIONS  
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
argon laser trabeculoplasty 
ALT/SGPT 
alanine aminotransferase/ serum glutamic-pyruvic transaminase 
AMD 
age-related macular degeneration 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
APAC 
Asia-Pacific (countries) 
AST/SGOT 
aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase 
ATE 
arterial thromboembolic events 
BCVA 
best corrected visual acuity 
BDRM 
blinded data review meeting 
β-HCG 
beta-human chorionic gonadotropin 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CFP 
color fundus photography 
CFT 
central foveal thickness 
cGE 
capillary gel electrophoresis 
CH1 
human constant heavy (domain) 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
CL 
human constant light (domain) 
CLBA 
competitive ligand binding assay  
Cmax 
maximum plasma concentration 
CNV 
choroidal neovascularization 
CORC 
Coimbra Ophthalmology Reading Center 
CRA 
clinical research associate 
CRC 
central reading center 
CRF 
case report form 
CRO 
contract research organization 
DA 
disc area(s) 
DME 
diabetic macular edema 
DP 
drug product 
DR 
diabetic retinopathy 
DS 
drug substance 
ECL 
Electrochemiluminescence 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEA 
European Economic Area 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ERG 
Electroretinogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FA 
fluorescein angiography 
Fab 
antigen binding fragment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 

 
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HPLC 
high performance liquid chromatography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IE 
Intercurrent Event 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IOL 
intraocular lens 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ISR 
injection site reaction 
IUD 
intrauterine device 
IVT 
Intravitreal 
IWRS 
interactive web response system 
LC-MS 
liquid chromatography-tandem mass spectrometry 
LDH 
lactate dehydrogenase 
MCH 
mean cell hemoglobin 
MCHC 
mean cell hemoglobin concentration 
mCNV 
myopic choroidal neovascularization 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm Hg 
millimeter(s) of mercury 
MoA 
mechanism of action 
MW 
molecular weight 
N 
number of subjects with an observation 
NAb 
neutralizing anti-drug antibody 
N 
number of subjects in the dataset or population 
OCT 
optical coherence tomography 
PDT 
photodynamic therapy 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
preferred term 
RBC 
red blood cell 
RGA 
reporter gene assay 
rhuMAb 
recombinant humanised monoclonal antibody 
RPE 
retinal pigment epithelium 
RVO 
retinal vein occlusion 
ROW 
SAE 
Rest of the World 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SLE 
slit lamp examination 
SLT 
selective laser trabeculoplasty 
SOC 
system organ class 
SOP 
standard operating procedure 
SPR 
surface plasmon resonance 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 

 
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Tmax 
time to maximum plasma concentration 
USP 
US Pharmacopoeia 
VA 
visual acuity 
VEGF 
Vascular Endothelial Growth Factor 
VH 
variable heavy (chain) 
VL 
variable light (chain) 
wAMD 
wet age-related macular degeneration 
WBC 
white blood cell 
WFI 
water for injection 
WHO 
World Health Organization 
WMA 
World Medical Association 
YAG 
yttrium aluminum garnet 
 
 

 
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6 
INTRODUCTION 
6.1 
Background: Disease 
Age-related macular degeneration (AMD) is a common eye condition that has been 
described as the leading cause of vision loss, affecting 10%–13% of adults over 
65 years of age in North America, Europe, Australia, and Asia.1 AMD is a progressive, 
degenerative disease affecting the macula, the region of the retina that is most important 
for visual acuity (VA). It causes damage to the macula, increasingly affecting sharp, 
central vision over time. While AMD by itself does not lead to complete blindness, the 
loss of central vision in AMD can interfere with simple everyday activities.2 Age is a 
major risk factor for AMD, with the disease most likely occurring after age 60. Other 
risk factors include smoking, race, and family history and genetics. 
 
Neovascular AMD is a major cause of loss of central vision in the elderly. While it does 
not cause complete blindness, it can make daily activities such as driving and reading 
difficult or impossible. Disease activity in neovascular AMD is lifelong. Even at late 
stages in the therapeutic course, exudative AMD patients remain at risk for substantial 
additional visual decline. AMD is a disease of the photoreceptors and the retinal 
pigment epithelium (RPE). In the aging eye, Bruch’s membrane composition changes, 
RPE function diminishes, and drusen (containing lipofuscin and other toxic waste 
products of metabolism) is deposited. Vision loss results from the abnormal growth and 
leakage of blood vessels in the macula. 
 
The main factor influencing AMD progression remains age, with genetics and smoking 
also having an impact. A meta-analysis of population-based AMD studies reported a 
global prevalence of 8.7% in people aged 45 to 85 years, with a higher prevalence in 
Europe and North America than in Asia.3 The authors further predicted that the number 
of cases worldwide would increase from 170 million in 2014 to 196 million in 2020 and 
288 million in 2040.  
 
AMD is divided into “early,” “intermediate,” and “late” types based on severity, with 
the late type being the most severe.2 The late type can be further divided into the dry 
(atrophic) and the wet (ie, neovascular or exudative) forms. The dry form is less 
aggressive and accounts for 90% of all AMD cases but only for 10% of cases of 
blindness due to AMD. Dry AMD may develop into wet AMD. Wet AMD (wAMD) 
affects 10% of the AMD patients and is the more aggressive form, which, if untreated, 
leads to rapid severe visual impairment and in many cases, legal blindness.1 However, 
80% to 90% of patients with severe vision loss due to AMD have wAMD.1  
 
Wet AMD causes rupture of Bruch’s membrane, an associated localized inflammatory 
response, and release of vascular endothelial growth factor (VEGF), which induces 
choroidal neovascularisation (CNV). The newly formed blood vessels grow through the 
ruptured membrane underneath the RPE and the retina. These new vessels are fragile 
and leak blood and proteins and may cause persistent edema below the macula, resulting 
in permanent damage to photoreceptors and the loss of central vision.  

 
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Treatment of wAMD includes photodynamic therapy (PDT) and laser coagulation, 
(although a recent Cochrane review found that laser coagulation is ineffective at 
preventing CNV and limiting loss of VA).4  
 
To date, standard of care treatment for wAMD is intravitreal (IVT) anti-VEGF therapy, 
with the VEGF-antagonist pegaptanib (Macugen®; Bausch + Lomb) and the monoclonal 
antibody ranibizumab (Lucentis®; Genentech/Novartis). Another anti-VEGF treatment 
for wAMD is aflibercept (Eylea®; Regeneron), which is a VEGF-trap that interferes 
with the biological actions by binding to VEGF-A, preventing it from interacting with 
its receptors. 
 
6.2 
Xlucane  
Xbrane Biopharma AB (referred to as Xbrane) is developing Xlucane as a proposed 
biosimilar candidate to the EU-licensed Lucentis® (ranibizumab). Lucentis was first 
approved as a treatment for wAMD in the United States in 2006 and the European 
Union/European Economic Area (EU/EEA) in 2007.5 
 
The active ingredient in Xlucane and Lucentis® is ranibizumab. Ranibizumab belongs to 
the pharmacological class of VEGF inhibitors and is an antigen binding fragment (Fab) 
of a recombinant humanized monoclonal antibody (rhuMAb) that binds to the receptor 
binding site of active forms of VEGF-A, including the biologically active, cleaved form 
of this molecule, VEGF110. VEGF-A has been shown to cause neovascularization and 
leakage in models of ocular angiogenesis and vascular occlusion and is thought to 
contribute to pathophysiology of neovascular wAMD. The binding of ranibizumab to 
VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and 
VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, 
vascular leakage, and new blood vessel formation.5  
 
Ranibizumab was originally developed from a murine monoclonal antibody produced 
using VEGF165-immunized mice.5 The variable light (VL) and variable heavy (VH) 
chain from the identified murine monoclonal antibody was fused to human constant 
light (CL) and human constant heavy (CH1) domains.5 The affinity of the new construct 
for VEGF165 was further optimized by phage display.6 Crystallographic studies show 
that the mature Fab fragment binds specifically to VEGF-A and that this interaction 
occurs at the residues Met81, Gln89, and Gly92 on VEGF-A.6,7 It should be noted that 
these residues are present in the 3 main VEGF-A isoforms in vivo (VEGF121, VEGF165, 
and VEGF110) and that they are required for binding to the VEGF-A receptors (VEGFR-
1 and VEGFR-2).6,8  
 
Prevention of VEGF-A binding to its receptors VEGFR1 and VEGFR2 on the surface 
of endothelial cells precludes endothelial cell proliferation and neovascularisation, as 
well as vascular leakage. Ranibizumab contains a light chain with 214 residues and a 
heavy chain containing 231 residues. In the fully assembled product, the 2 polypeptide 
chains are linked via a disulfide bond. In addition to the interchain disulfide bond, there 

 
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are 2 intrachain disulfide bonds in each polypeptide chain. In a nonreduced 
environment, the fully assembled product has a molecular weight (MW) of 
approximately 48 kDa; after reduction, both polypeptide chains can be detected 
separately (light chain 23 kDa and heavy chain 25 kDa). 
 
6.2.1 Quality Development 
Xlucane has been developed with patented technology and deep knowledge and 
experience in protein production, resulting in a very high production yield—currently 
on average 8× what a standard system in Escherichia coli (BL21) would result in. 
 
The manufacturing process for ranibizumab in Xlucane has been developed in-house by 
Xbrane (Stockholm, Sweden). As with Lucentis®, ranibizumab is produced in an E coli 
K-strain but with differences in the strain background and in the expression vector. 
 
The formulation for Xlucane drug substance (DS) is being developed with a 
composition of 20 mg/mL ranibizumab, α,α-trehalose dihydrate, histidine hydrochloride 
monohydrate, histidine, polysorbate 20, and water for injection (WFI). All excipients 
are of pharmacopoeial grade.  
 
The formulation for Xlucane drug product (DP) is being developed to replicate that of 
Lucentis® with a composition of 10 mg/mL ranibizumab, α,α-trehalose dihydrate, 
histidine hydrochloride monohydrate, histidine, polysorbate 20, and WFI. All excipients 
are of pharmacopoeial grade.  
 
Batches of Xlucane DS, produced at 300 L scale, and Xlucane DP, using the DS 
material manufactured at the 300 L scale, have been analyzed extensively for 
comparative physiochemical and functional similarity assessment studies. Biosimilarity 
between the Xlucane and Lucentis® has been demonstrated in a stepwise procedure.  
 
6.2.2 
Summary of Nonclinical Development 
Physicochemical characterization of Xlucane and Lucentis® was performed to enable 
comparison of the structural characteristics of the protein products (eg, the primary and 
higher order structures and protein variants). Functional in vitro assays representative of 
biological activity were part of the similarity assessment program. Protein and process 
related impurities were also characterized, quantified, and compared. 
The methods used for the characterization of Xlucane were chosen to provide a 
thorough understanding of the similarity and potential differences between Lucentis® 
and Xlucane. In addition to the batches used, isolates from different purification steps 
were also used in initial studies for optimization of the analytical methods. Using these 
extra isolates, different forms of the target molecule were detected, further supporting 
the sensitivity of the methods used.  

 
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Extensive analyses show that the produced Xlucane lots and the analyzed Lucentis® 
batches were similar for the tests performed. Some analytical tests are ongoing and 
results are pending. 
6.2.2.1 Primary and Higher Order Structures 
The amino acid sequence of Xlucane was analyzed by liquid chromatography-tandem 
mass spectrometry (LC-MS) on protease degraded material, and was shown to be 
identical to that of Lucentis®. The primary structure for Lucentis® and Xlucane was 
analyzed using reduced/non-reduced conditions in combination with LC-MS for intact 
mass of the full Fab or for the individual subunits confirming expected mass in all 
samples tested. C-terminal sequence for light chain and heavy chain was confirmed in 
both Xlucane and Lucentis® using LC-MS/MS. Overall, the primary structure in 
Xlucane DS and DP is similar to the primary structure of Lucentis®.  
Secondary and tertiary structure for Lucentis® and Xlucane material was analyzed and 
used to characterize the higher order structure. Overall methods showed that the higher 
order structure of Xlucane is similar to the higher order structure of Lucentis®. 
6.2.2.2 Purity/Impurity Profile 
Purity and impurities such as high molecular weight species, fragments, oxidized, 
deamidated, gluconoylated, pyroglutamated species were analyzed by size exclusion 
high performance liquid chromatography (HPLC), reversed phase HPLC, ion exchange 
HPLC, analytical ultra-centrifugation, reducing/non-reducing capillary gel 
electrophoresis (cGE), capillary isoelectric focusing (cIEF), and LC-MS. All methods 
showed that Xlucane and Lucentis® have a similar purity/impurity profile.  
Process-related impurities such as host cell DNA, bacterial endotoxin, and sterility were 
analyzed by RT-PCR, LAL assay (Ph. Eur. 2.6.14, USP <85>), and membrane filtration 
(Ph. Eur. 2.6.1, USP <71>). Host cell DNA specifications have been set based on 
industry standards (there are no pharmacopoeial standards), and all results are below 
this limit. All other methods showed that Xlucane are within the specifications of EU 
and US Pharmacopoeial standards. 
 
Host cell proteins (HCPs) have been analyzed with commercially available K12 HCP 
enzyme-linked immunosorbent assay (ELISA) kits. The method shows that levels of 
HCPs are within the specifications of industry standards (there are no pharmacopoeial 
standards). Xbrane is currently developing a specific HCP ELISA kit for the used 
process, and all clinical batches will be analyzed with this method prior to the start of 
the trial. Subvisible particles were also measured for Xlucane DP material, and the 
amount of subvisible particles is within the specifications of US Pharmacopoeial 
standards (USP <789>). Xbrane is currently developing an ELISA method for detection 
of Protein L from the first purification step. All clinical batches will be analyzed with 
this method prior to the start of the trial.  
 

 
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6.2.2.3 Potency and Binding 
Xbrane has conducted surface plasmon resonance (SPR/BIAcore) and HEK293 reporter 
gene assay (RGA) with Xlucane and Lucentis® to evaluate potential differences in the 
content and functionality of ranibizumab. The HEK293/RGA will continue to be used in 
lot release and stability testing, and SPR/BIAcore will also be used for extended 
characterization. 
Xlucane has been investigated for its binding capacity to VEGF165, VEGF110, VEGF121 
and VEGF189 and compared to that of Lucentis®. Specific interaction with VEGF-A is 
crucial for the action of Lucentis® and Xlucane and this mechanism of action (MoA) 
has been examined using BIAcore. BIAcore was used to provide quantitative data on 
the association rate constant for the binding of ranibizumab to each of the VEGF 
variants (VEGF165, VEGF110, VEGF121 and VEGF189). Xbrane has demonstrated that the 
binding characteristics of Xlucane to VEGF165, VEGF110, VEGF121 and VEGF189 by 
means of SPR/BIAcore are comparable to that of Lucentis®.  
 
The HEK293/RGA assay was also used to assess similarity with respect to potency 
between batches of Xlucane DS and Xlucane DP, formulated as described in Section 
6.2.1, and Lucentis® batches. The RGA was used to represent a relevant signal 
transduction pathway (VEGF165, VEGF110, VEGF121 and VEGF189). The interaction 
between VEGF165, VEGF110, VEGF121 and VEGF189 and the VEGF-AR2 (KDR) 
receptor in HEK293 cells (GloResponse™ Cell Line) was quantified. Results from the 
RGA show that the potency is similar for Xlucane and Lucentis for all isoforms. The 
assay has been fully validated for VEGF165 and qualified for all other isoforms. 
 
6.2.2.4 Pharmacokinetic Study in Rabbits 
In addition, to support the development of Xlucane for registration in India and Japan as 
well as other regions such as China, an in vivo pharmacokinetic (PK) study was 
conducted in New Zealand White rabbits (data on file; forthcoming).9 The main 
objective of the study was to compare the PK characteristics of 2 formulations of 
ranibizumab (biosimilar [Xlucane] and Lucentis®) at a dose level of 0.5 mg (per eye) 
following a single bilateral intravitreal injection. The study design is shown in Table 1. 

 
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Table 1: Experimental Design of Rabbit PK Study 
Group 
No. 
Test 
Material 
Dose 
Level 
(mg/eye) 
Dose 
Volume 
(µL/eye) 
Dose 
Concentration 
(mg/mL) 
No. of Males 
PK/Termination Time Point 
Day 2a 
Day 14 
Day 28 
1 
Lucentis® 
0.5 
50 
10 
2 (4 eyes 
for PK) 
2 (4 eyes 
for PK) 
4 (4 eyes 
for PK; 4 
eyes for 
histo) 
2 
Xlucane 
0.5 
50 
9.8 
2 (4 eyes 
for PK) 
2 (4 eyes 
for PK) 
4 (4 eyes 
for PK; 4 
eyes for 
histo) 
Abbreviation(s): h = hour; histo = histology; No. = number; PK = pharmacokinetic. 
a Day 2, at 24 h ± 1 h postdose. 
During the course of the study, the animals were monitored for mortality/moribundity, 
abnormal clinical signs, inappetence, body weights, ophthalmology, and 
electroretinograms (ERGs). Serum and ocular tissues were collected for measurement of 
ranibizumab concentration and pharmacokinetics. At scheduled termination, ocular 
tissues (right eye) were collected from microscopic evaluation. 
There was no mortality during the course of the study. There were no abnormal clinical 
signs/appetence nor changes in the body weights/body weight gains or ERG parameters 
that could be attributed to a single bilateral IVT of biosimilar Xlucane or Lucentis® at 
dose level of 0.5 mg/eye. Ocular changes attributed to the administration of Lucentis® 
were limited to a transient inflammation of the anterior chamber in 2/16 eyes (2/8 
animals) on Day 14. By Day 28, signs of anterior uveitis were not observed in any of 
the 4 surviving animals, but changes in the posterior segment, notably the presence of 
cell-like opacities in the anterior portion of the vitreous, and deeper, larger vitreal 
opacities were present in 1/8 Lucentis®-treated animals (both eyes). The administration 
of Xlucane was well tolerated, with no ocular inflammation observed in any of the eyes 
treated.   
A comparable exposure (Cmax and AUC(0-t)) in serum and ocular tissues was observed in 
animals that received Xlucane compared to Lucentis®. Tmax was generally observed at 
the last time point collected (24 hours postdose) or at the last quantifiable value 
(48 hours postdose) for serum. Tmax was observed at 24 hours postdose in ocular tissues 
(vitreous humour and sensory retina). At 24 hours postdose, the highest exposure (Cmax 
and AUC(0-t)) was found in vitreous humor, followed by the sensory retina and then the 
serum. When estimated for vitreous humor, the T1/2 was 71.9 hours for Lucentis® and 
72.4 hours for Xlucane.   
Microscopic changes of the right eye of animals treated with Xlucane or Lucentis® were 
limited to mononuclear cell infiltration. The incidence and severity of this change was 
generally higher in the Lucentis® group (minimal to moderate severity; 7 ocular tissues 
affected) when compared to the Xlucane group (minimal severity; 3 ocular tissues 
affected).   
In conclusion, a single bilateral IVT injection of 1 of 2 formulations of ranibizumab 
(biosimilar Xlucane or Lucentis®) to New Zealand white rabbits was well tolerated, 

 
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with no compound-related clinical signs or changes in the body weights, appetite, or 
ERGs. The systemic exposure (Cmax and AUC(0-t)) in serum and local exposure in ocular 
tissues in animals treated with Xlucane 0.5 mg/eye (or 1 mg/total) was comparable to 
animals treated with Lucentis® 0.5 mg/eye (or 1 mg/total). Microscopic changes of the 
right eye of animals treated with Xlucane or Lucentis® were limited to mononuclear cell 
infiltration. The incidence and severity of this change was generally higher in the 
Lucentis® group (minimal to moderate severity; 7 ocular tissues affected) when 
compared to the Xlucane group (minimal severity; 3 ocular tissues affected).     
 
6.2.3 Planned Clinical Study 
Xlucane has not yet been tested in any clinical study. The planned clinical development 
includes this pivotal phase III study to evaluate the efficacy, equivalence, PK, 
immunogenicity, and safety of Xlucane and Lucentis®. The clinical study is planned to 
be conducted in the EU, US, APAC, and other regions to confirm the biosimilarity of 
Xlucane to Lucentis®.  
 
The clinical phase III study is a double-blind (double-masked), multicenter, parallel 
group study in patients with wAMD. The patients will be randomized 1:1 to receive 
Lucentis® or Xlucane. The patients will receive 13 doses of Xlucane or Lucentis® and 
be followed for changes in efficacy and safety for 52 weeks. The primary endpoint is 
change in best corrected visual acuity (BCVA) letters at Week 8 compared to Baseline 
using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. 
Approximately 580 patients will be randomized in the study. Refer also to Section 8.2 
of the protocol for study design discussion. 
Immunogenicity will be evaluated by anti-drug antibody (ADA) formation and 
neutralizing anti-drug antibody (NAb) up to Week 52 after Randomization. An 
electrochemiluminescence (ECL) bridging assay format that uses labelled (biotinylated 
and ruthenylated) Xlucane will be employed for screening, with confirmatory and 
titration tiers for ADA performed. The characterization of NAb will be performed using 
a Competitive Ligand Binding Assay format (CLBA) that will measure the capacity of 
the test samples to inhibit binding of Xlucane to biotinylated VEGF-165 immobilized 
on streptavidin-coated plates.  
A PK substudy is incorporated in the proposed phase III clinical trial to permit an 
assessment for similarity in systemic exposure following Xlucane and Lucentis® 
administration. It is anticipated that the systemic exposure should be low, given the dose 
and route of administration. Between approximately 40 and 60 patients will be included 
in the PK sub-study. The collection of PK samples is proposed for immediately before 
the first dose, at 23 hours after the first dose (Day 1), and at 23 hours after the sixth dose 
(Week 20); Tmax is around 22 hours. 
6.3 
Lucentis® (ranibizumab injection) 
Lucentis® (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype 
monoclonal antibody fragment designed for intraocular use. Lucentis® is indicated for 

 
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the treatment of patients with: wAMD; macular edema following RVO; DME; diabetic 
retinopathy (DR); and myopic CNV (mCNV). The active substance of Lucentis® is 
ranibizumab, a monoclonal antibody fragment.5  
The mode of action of ranibizumab is to bind to the vascular endothelial growth factor 
A (VEGF-A) present in the eyes of the affected patients. VEGF-A has been shown to 
cause neovascularization and leakage in models of ocular angiogenesis and vascular 
occlusion and is thought to contribute to pathophysiology of neovascular AMD, mCNV, 
DR, DME and macular edema following RVO. The binding of ranibizumab to VEGF-A 
prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the 
surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, 
and new blood vessel formation. 
Ranibizumab, which lacks an Fc region, has a molecular weight of approximately 48 
kilodaltons and is produced by an E coli expression system in a nutrient medium 
containing the antibiotic tetracycline. Tetracycline is not detectable in the final product. 
6.3.1 Nonclinical Studies  
Animal studies have not been conducted to determine the carcinogenic potential of 
ranibizumab. Based on the anti-VEGF mechanism of action of ranibizumab, treatment 
with Lucentis® may pose a risk to reproductive capacity. 
6.3.1.1 Infertility 
No studies on the effects of ranibizumab on fertility have been conducted and it is not 
known whether ranibizumab can affect reproduction capacity. Based on the anti-VEGF 
mechanism of action for ranibizumab, treatment with Lucentis® may pose a risk to 
reproductive capacity. 
 
6.3.2 Clinical Studies in wAMD 
The safety and efficacy of Lucentis® were assessed in three randomized, double-
masked, sham- or active-controlled studies in patients with wAMD. A total of 1323 
patients (Lucentis® 879, control 444) were enrolled in the three studies.  
In studies AMD-1 and AMD-2 the primary efficacy endpoint was the proportion of 
patients who maintained vision, defined as losing fewer than 15 letters of visual acuity 
at 12 months compared with Baseline. Visual acuity was measured at a distance of 2 
meters. Almost all Lucentis®-treated patients (approximately 95%) maintained their 
visual acuity. Among Lucentis®-treated patients, 31% to 37% experienced a clinically 
significant improvement in vision, defined as gaining 15 or more letters at 12 months. 
The size of the lesion did not significantly affect the results. Further, patients in the 
group treated with Lucentis® had minimal observable CNV lesion growth, on average. 
At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas 
(DA) for Lucentis® versus 2.3-2.6 DA for the control arms. At Month 24, the mean 

 
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change in the total area of the CNV lesion was 0.3-0.4 DA for Lucentis® versus 2.9-3.1 
DA for the control arms. 
In study AMD-3, the primary efficacy endpoint was the mean change in visual acuity at 
12 months compared with Baseline. Visual acuity was measured at a distance of 4 
meters. After an initial increase in visual acuity (following monthly dosing), on average, 
patients dosed once every 3 months with Lucentis® lost visual acuity, returning to 
Baseline at Month 12. In study AMD-3, almost all Lucentis®-treated patients (90%) lost 
fewer than 15 letters of visual acuity at Month 12. 
In study AMD-4, clinical results at Month 24 remain similar to that observed at Month 
12. From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 
mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm. 
Visual acuity was measured at a distance of 4 meters. 

 
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7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objective of the study is to demonstrate that the biosimilar candidate 
Xlucane is equivalent to Lucentis® in subjects with wAMD as assessed by the change in 
BCVA from Baseline to Week 8. 
7.2 
Secondary Objectives 
The secondary objectives of the study are as follows:  
• Evaluate the efficacy of Xlucane vs Lucentis® in subjects with wAMD based on 
central foveal thickness (CFT) measured by spectral domain optical coherence 
tomography (SD-OCT), area of choroidal neovascularization, and presence of 
leakage assessed by fundus fluorescein angiography (FA) 
• Evaluate the safety of Xlucane vs Lucentis® 
• Evaluate the systemic exposure of Xlucane vs Lucentis® in subjects participating in 
pharmacokinetics (PK) evaluation 
• Evaluate immunogenicity (ie, anti-ranibizumab antibodies and NAb) of Xlucane vs 
Lucentis® 

 
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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a phase III multicenter, double-blind (double-masked), randomized, parallel 
group study in subjects with wAMD. Approximately 580 subjects will be enrolled and 
randomized in a 1:1 ratio to receive either Lucentis® (0.05 mL of 10 mg/mL 
ranibizumab) or the investigational product (IP), Xlucane (0.05 mL of 10 mg/mL 
ranibizumab), in the study eye once every 4 weeks for 52 weeks (ie, 12 months).  
The study eye will be defined as the eye meeting all of the inclusion criteria and none of 
the exclusion criteria (ie, the enrollment criteria).  
The assigned study drug will be administered as an ophthalmic intravitreal (IVT) 
injection. Designated, unmasked study staff will prepare and administer the study drug, 
ensuring that the masking of the subject is maintained during the injection procedure. 
See Section 8.4.6. 
Subjects will be randomized by interactive web response system (IWRS) to receive 
13 doses of either Xlucane or Lucentis® in the study eye. The randomization scheme 
will automatically ensure that the study drug assignment for a given subject is random 
and that an overall 1:1 ratio of assignments to each of the 2 study drug treatments is 
approximated. In addition, the randomization scheme will include the following 
stratification parameters to ensure balanced distribution of assignment to the 
2 treatments: eye color (light iris vs dark iris), geographical region where enrolled and 
the BCVA letters at Baseline (55 or lower, 56 to 65, 66 or higher). Subjects will be 
followed up for changes in efficacy variables and safety for 52 weeks. Each subject’s 
involvement will last up to approximately 52 weeks (ie, 12 months). 
At the beginning of the study, a subgroup of between approximately 40 and 60 subjects 
at a select number of participating sites will be sequentially asked to participate in an 
evaluation of PK. This subgroup will be asked to provide blood samples for 
measurement of plasma ranibizumab immediately before administration of the first dose 
of Xlucane or Lucentis®. Additional samples will be collected 23 hours after the first 
dose (ie, Day 1) and 23 hours after the sixth dose (ie, Week 20) at expected time to 
maximum plasma concentration (Tmax, which is around 22 hours). The primary analysis 
set will be the Per-Protocol population. 
An interim analysis will be performed on unmasked study data. After all of the 
randomized subjects have 6-month (ie, 24 weeks) data available, an unmasked analysis 
of efficacy and safety endpoints as well as PK and immunogenicity will be performed. 
The aim of the unmasked analysis is to initiate the submission of the application for 
marketing authorization as agreed with the European Medicines Agency. This analysis 
will not affect the further conduct of the study. 

 
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FA, CFP, and OCT will be performed at Screening. The images will be sent to the central 
reading center (CRC) for interpretation and confirmation of eligibility. The CRC will also 
grade images that are collected during the study.  
 
Figure 1 Study Design 
 

 
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8.1.1 Schedule of Assessments 
 
Assessment(s) 
Pre-treatment 
Treatment Period 
End of 
Treatment21  
Visit(s) 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 to 1519 
16 
Time point 
Screening 
Day 0/ 
BL 
Week  
2 
Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 28 to  
Week 4819 
Week 52 
Window (± days) 
≤ 21 days 
before start of 
treatment 
± 2 days ± 2 days ±2 days ± 5 days ± 5 days ± 5 days ± 5 days 
± 5 days 
± 5 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic data (such as, 
ethnic origin, date of birth, and 
sex) 
X 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination2 
X2 
 
 
 
 
 
 
 
 
 
X2 
Body mass index (height and 
weight measured) 
X 
 
 
 
 
 
 
 
 
 
 
SLE3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated fundus examination4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
IOP measurement5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
CFP6 
X8 
 
 
 
 
 
 
 
X 
 
X 
FA7 
X8 
 
 
 
 
 
 
 
X 
 
X 
OCT9 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA by ETDRS (including 
manifest refraction)10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs11 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 

 
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Assessment(s) 
Pre-treatment 
Treatment Period 
End of 
Treatment21  
Visit(s) 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 to 1519 
16 
Time point 
Screening 
Day 0/ 
BL 
Week  
2 
Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 28 to  
Week 4819 
Week 52 
Window (± days) 
≤ 21 days 
before start of 
treatment 
± 2 days ± 2 days ±2 days ± 5 days ± 5 days ± 5 days ± 5 days 
± 5 days 
± 5 days 
Hematology12 
X 
 
 
X 
X 
X 
 
 
X 
(X)20 
X 
Clinical chemistry13 
X 
 
 
X 
X 
X 
 
 
X 
(X)20 
X 
Urine pregnancy test14 
Country specific requirements exist 
(see notes) 
X 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Subgroup ONLY: PK 
sampling15 
 
X15 
 
 
 
 
 
X15 
 
 
 
Blood sample collection for 
immunogenic evaluation16 
 
X17 
 
X17 
X17 
X17 
 
X17 
X17 
(X)17 
X17 
Study drug administration18 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event reporting 
X (including BL 
events) 
X-----------------------------------------------------------------------------------------------------X 
Injection site reactions 
 
X 
 
X----------------------------------------------------------------------------------------X 
Concomitant medications 
X 
X 
X-----------------------------------------------------------------------------------------------------X 

 
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Abbreviations: BCVA = best corrected visual acuity; BL = Baseline; CFP = color fundus photography; CRC = central reading center; EOT = 
end of treatment; ETDRS = Early Treatment Diabetic Retinopathy Study; FA = fluorescein angiography; IOP = intraocular pressure; 
IVT = intravitreal; NAb = neutralizing anti-drug antibody; OCT = optical coherence tomography; PE = physical examination; PK = 
pharmacokinetic; SLE = slit lamp examination. 
 
Notes:  
1. Collect full medical history, historical disease data, diagnostic information, and concomitant illnesses/diseases, adverse events (including 
Baseline events), and concomitant medications. 
2. A PE will consist of a routine evaluation of organ systems (including head, ears, eyes, nose, throat, neck, cardiovascular, pulmonary, 
abdomen, skin, extremities, neurological, lymph nodes, and musculoskeletal). At the Screening Visit, the PE will include the collection of the 
subject’s eye color (ie, light iris or dark iris). At the Week 52/EOT Visit, the PE will also include a query of the patient to determine if 
changes in his/her physical condition have occurred since the PE at Screening. 
3. SLE of the anterior segment is conducted in both eyes at Screening and prior to Randomization on Day 0. At all other scheduled visits, SLE 
is conducted in the study eye only. 
4. Dilated fundus examination of the posterior segment is conducted in both eyes at Screening and prior to Randomization on Day 0. At all 
other scheduled visits dilated fundus examination is conducted in the study eye only. 
5. IOP is measured in both eyes at Screening, prior to Randomization on Day 0, and at Week 52 (or EOT visit). At all other scheduled visits, 
IOP is measured in the study eye only. At pre-injection, IOP should be measured using the Goldmann tonometry method. After IVT injection 
(eg, 30 minutes post injection), non-contact tonometry may be used, but in the event IOP is greater than 36 mm Hg, it is recommended to 
perform IOP measurement with Goldmann or Tonopen or ICare (applanation tonometer) within the next 30 minutes. 
6. CFP assessment is conducted in both eyes at Screening. At Week 24 and 52 (or EOT visit), CFP assessment is conducted in the study 
eye only. Images should be sent to the CRC. 
7. FA assessment is conducted at Screening,  Week 24 and 52 (or EOT visit), Images of both eyes should be sent to the CRC for these visits. FA 
Grading by CRC is conducted on both eyes at Screening Visit and in the study eye only at Week 24 and 52 (or EOT visit). 
8. Assessments to be confirmed by the CRC during Screening and prior to Randomization. 
9. OCT assessment is conducted in both eyes at Screening and BL. At all other visits, including Week 52 (or EOT visit), OCT assessment is 
conducted in the study eye only. Images should be sent to the CRC. 
10. BCVA assessment by ETDRS at 4 meters, including manifest refraction.  
11. Vital signs measurements to include heart rate and blood pressure. Systolic and diastolic blood pressure and pulse rate will be measured after 
patients have been at rest (seated) for at least 5 minutes. 
12. Hematology panel evaluations will be sent to a central laboratory. See also Section 10.1.4.2.3. Results from Screening visit must be reviewed 
by the investigator before patient is randomized 

 
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13. Clinical chemistry panel evaluations will be sent to a central laboratory. See also Section 10.1.4.2.3. Results from Screening must be 
reviewed by the investigator before patient is randomized 
14. Urine pregnancy test for females of childbearing potential (only), must be negative for the patient to receive study medication. Country 
specific requirement: It must be noted that sites in Czech Republic must perform urine pregnancy test every 2 months in addition to 
Screening and Week 52 (EOT visit)- This includes Week 8, Week 16, Week 24, Week 32, Week 40 and Week 48. (Please refer to CRF 
completion guidelines for documenting these visits) 
15. See Schedule in Section 8.1.2 for details on timing of PK sampling relative to study drug injection. 
16. Additional samples for monitoring immunogenicity testing are collected from subjects with any sign(s) of intraocular inflammation, as these 
may indicate an immune reaction. 
17. Blood sampling for immunogenic (ie, anti-ranibizumab antibodies and NAb) testing must be performed before dosing on Day 0, Week 4, 
Week 8, Week 12, Week 20, Week 24, Week 36, and Week 52. 
18. Study drug administration in study eye only, per randomized assignment. After the injection, monitor the subject for any signs or symptoms 
for at least 60 minutes.  
19. Visits 10, 11, 12, 13, 14, and 15 (Week 28, 32, 36, 40, 44, and 48) should each continue to occur monthly (ie, every 4 weeks). 
20. During Visits 10 to 15 (Week 28 to Week 48), hematology and clinical chemistry panel evaluations should occur at Visit 12 (Week 36).  
21. EOT assessments may also be performed for early discontinuation or withdrawal from the study. 
 
 
 

 
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8.1.2 Schedule of Additional Assessments for PK Subgroup ONLY  
Visit(s) 
2 
2b2 
8b3 
Time point 
Day 0 
Day 12 
(Week 20)3 
Blood Sampling Window (±) 
≤ 60 minutes  
Predose 
23 hours ± 60 minutes  
Postdose 
23 hours ± 60 minutes  
postdose 
Blood sample(s) for PK evaluation 
X1 
X 
X3 
IOP measurement4 
 
X 
X 
SLE5 
 
X 
X 
Adverse event reporting 
 
X 
X 
Abbreviations: IOP = intraocular pressure; PK = pharmacokinetic; SLE = slit lamp examination. 
Notes:  
1. Day 0 PK blood sampling must be performed ≤ 60 minutes before the first IVT injection of study medication.  
2. Day 1 PK blood sampling must be performed 23 hours (± 60 minutes) after the IVT injection (ie, first dose of study medication). 
3. Week 20 PK blood sampling must be performed 23 hours (± 60 minutes) after the IVT injection (ie, sixth dose of study medication). 
4. IOP is measured by tonometry in the study eye only. Non-contact tonometry may be used, but in the event IOP is greater than 36 mm Hg, it is 
recommended to perform another IOP measurement with Goldmann or Tonopen or ICare (applanation tonometer) within the next 30 minutes. 
5. Slit lamp examination of the anterior segment is conducted in the study eye only. 
 
 

 
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8.2 
Discussion of Study Design 
8.2.1 Study Design 
The objectives of this study are to demonstrate the equivalence11 of Xlucane to 
Lucentis® and to evaluate the safety and efficacy of Xlucane as compared to Lucentis® 
(ranibizumab injection). This will be done through a multicenter, randomized, double-
blind (double-masked), parallel group study. The rationale for the design of this trial is 
to appropriately evaluate Xlucane as compared to Lucentis®, the reference standard 
for wAMD.  
The selected endpoints for demonstrating equivalence of Xlucane to Lucentis® are in 
accordance with current standards, as are the safety endpoints of the trial. Masking 
subjects and designated study team members to the treatment assignment(s) ensures 
objectivity and minimizes bias. Randomization through the IWRS guards against 
selection bias.  
The selected dosing schedule of the 2 study drugs is based upon clinical studies with 
Lucentis®, whereby monthly dosing is expected to maintain visual acuity and to result 
in an additional average 1 to 2 letter gain. Furthermore, prespecified safety evaluations 
will monitor subjects for any adverse events and injection site reactions (ISRs) during 
and after treatment. 
Biosimilarity will be concluded if the two-sided 90% (US FDA) or 95% (ROW) 
confidence interval (CI) for the difference in mean change in BCVA at Week 8 between 
the Xlucane and Lucentis® is confined within the equivalence margin of ± 3.5 letters. The 
difference in the approach around the confidence interval is based on the regulatory 
requirement in United States (90% CI) and the rest of the world (95% CI), as agreed with 
the relevant regulatory authorities. 
A meta-analysis of ANCHOR18 and MARINA10 studies was done in order to focus on 
Week 8 BCVA data and ensure that the proposed equivalence margin will preserve at 
least 50% of the lower limit of the 95% confidence interval for the difference in mean 
change in BCVA between treatment and placebo which was 7.7 (Table 2). 
 
 
 
 

 
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Table 2 Meta-analysis wAMD Ranibizumab Studies using BCVA change at 8 
weeks  
 
Study 
Experimental 
Control 
95% CI 
Weight 
(fixed) 
N 
Mean 
SD 
N 
Mean SD MD lower upper 
MARINA 
240 
5.4 
9.3 
238 
-2.2 
8.4 
7.6 
6.09 
9.11 
62.9% 
ANCHOR 139 
9.8 
11.83 143 
-1.8 
15 11.6 
8.08 
15.12 
37.1% 
 
379 
 
 
381 
 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI 
 
 
 
 
 
 
 
 
MD lower upper  
 
 
 
 
Fixed effects 
model 
9.08 7.70 
10.47 
 
An equivalence margin of  ±3.5 letters represents at least 55% of the lower limit of the 
95% confidence interval of treatment benefit (7.7 letters) demonstrated above. 
Considering this and that the minimal clinically important difference in VA has 
previously been set to or estimated to be 5 to 10 letters,12,13,14 an equivalence margin of 
±3.5 letters is deemed adequate and supported by EMA/FDA in recent scientific advice. 
As the primary objective of the study is to demonstrate equivalence of Xlucane versus 
Lucentis®, a symmetrical equivalence region of ±3.5 letters will be used. Biosimilarity 
will be concluded if the two-sided 95% or 90% CI for the difference between Xlucane 
and Lucentis in the BCVA change from Baseline at Week 8 is confined within the 
equivalence margin of ± 3.5 letters. 
The study is also aimed to detect any notable differences in plasma ranibizumab levels 
between the 2 products, Xlucane and Lucentis®. Systemic ranibizumab exposure is very 
low after IVT injection, and there are potential issues in detecting such low levels by an 
assay. Further considering the approach that any notable differences are more easily 
detectable at steady-state, when ranibizumab concentrations are higher (ie, near the 
expected Tmax after dosing, which is around 22 hours), the current study has PK 
measurements at Baseline, Day 1 (23 hours [± 60 minutes] after the first dose), and at 
Week 20 (23 hours [± 60 minutes] after the sixth dose) to possibly detect any 
differences in peak systemic exposure between the 2 products. 
The rationale for the design of this trial is to appropriately evaluate Xlucane as 
compared to Lucentis®, the current standard of care for wAMD. The clinical relevance 
for selecting the endpoints of BCVA (using ETDRS) and changes in CFT, area of CNV, 

 
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and leakage from CNV lesion(s) is founded upon multiple studies.5 Similarly, in 
Lucentis® clinical studies, VA was measured at a distance of 4 meters (or less) relative 
to ETDRS. Increased retinal thickness (ie, CFT) and leakage from CNV are well 
associated with wAMD. All are common causes of severe vision loss and thus changes 
in these measures can be considered objective endpoint evaluations for wAMD. 
Refer also to Section 6.2 of the protocol.  
8.3 
Selection of Study Population 
8.3.1 Number of Planned Subjects  
It is anticipated that approximately 580 subjects will be enrolled and randomized. 
There are approximately 160 sites anticipated to participate in approximately 15 
countries in the United States, Europe, the Middle East, and Asia-Pacific. 
Refer also to the statistical considerations in Section 11.4, on which the numbers 
are based.  
Rescreening will be allowed for subjects previously determined as screen failures due to 
inclusion and/or exclusion criteria that could transiently change and do not compromise 
the subject’s safety. Only one rescreen will be allowed per subject. When a rescreen is 
authorized by the Sponsor or its designee, the subject is to be reconsented, and all 
screening procedures (ie, laboratory testing, OCT, and color fundus photography [CFP]) 
should be repeated/completed and provided to the CRC, with the exception of the FA 
procedure. Based on the CRC’s determination, screening FA may not need to be 
repeated. Thus, if the CRC deems it appropriate/acceptable, prior FA performed at 
the time of the screen failure, may therefore be used for eligibility assessment. 
However if more than 30 days have passed since subject was screen failed, all 
procedures including FA must be repeated. Subjects who discontinue the study after 
Randomization and after receiving study medication are not eligible for rescreening. 
 
8.3.2 Inclusion Criteria 
To be eligible for study entry, subjects must satisfy all of the following inclusion 
criteria: 
1. Written and signed informed consent form obtained at Screening before any study-
related procedures are performed. Patients must be capable of providing their own 
consent (an impartial witness must be present in case of illiterate patients). 
2. Willingness and ability to undertake all scheduled visits and assessments as judged 
by the investigator. 

 
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3. Newly diagnosed, active subfoveal choroidal neovascularization (CNV) lesion 
secondary to age-related macular degeneration (AMD) in the study eye. Note: active 
CNV indicates the presence of leakage as evidenced by fluorescein angiography (FA) 
and intra- or subretinal fluid as evidenced by optical coherence tomography (OCT), 
which must be confirmed by the central reading center during Screening: 
a. The area of CNV must be ≥ 50% of the total lesion area in the study eye, and  
b. Total lesion area ≤ 9.0 disc areas (DA) in size (including blood, scars, and 
neovascularization) as assessed by FA in the study eye  
4. BCVA of ≤ 73 and ≥ 49 ETDRS letter score in the study eye using the ETDRS chart 
(20/40 to 20/100 Snellen equivalent) at Screening. 
5. Fellow eye should not be expected to need any anti-VEGF treatment for the duration 
of study participation based on Investigator´s decision. 
6. Age ≥ 50 years at Screening. 
7. Male and female subjects of childbearing potential must be willing to completely 
abstain or agree to use an appropriate method of contraception from the time of 
signing the informed consent form and for the duration of study participation through 
3 months after the last dose of study drug. See Appendix 17.1 for examples of 
acceptable contraception. (The investigator and each subject will determine the 
appropriate method of contraception for the subject during the participation in the 
study.) 
a. A woman of childbearing potential is any woman, regardless of sexual 
orientation, who meets the following criteria: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 12 consecutive months (ie, has had menses at any 
time in the preceding 12 consecutive months). 
b. A man of sexual potential is any man who has not been surgically sterilized 
(eg, has not undergone bilateral orchiectomy). 
  
8.3.3 Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following exclusion 
criterion is applicable: 
1. Any previous intervention, including pharmacological treatment, laser, and/or surgery 
for wAMD in either eye; (Exception: Vitamin supplementation for AMD prevention). 
(In case of end stage wAMD in fellow eye where anatomical and functional status 
diagnosed on Screening, disqualifies subject from intravitreal anti-VEGF treatment 
according to local medical standards of care, the previous laser photocoagulation or 
PDT procedure in fellow eye performed for wAMD treatment is allowed). (This 

 
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criterion is not applicable for fellow eye, in case of subjects who have only one eye 
or the fellow eye fulfills additional criteria specified in Section 8.3.4). 
2. Any previous vitreoretinal surgery in the study eye for any cause. 
3. Any previous IVT treatment, including any anti-VEGF medications, steroids, and/or 
any other investigational medication in either eye. 
4. The use of long-acting steroids, either systemic or intraocular in any eye, in the 
18 months before planned initiation of study treatment. (Note: Current or planned 
Iluvien® [fluocinolone acetonide intravitreal], implantation during the study is 
prohibited.) 
5. Subfoveal fibrosis, subfoveal atrophy, and/or scarring extending > 50% of total lesion 
area in the study eye as assessed by the investigator at Screening and confirmed by 
the central reading center prior to Randomization. 
6. Choroidal neovascularization in either eye due to non-AMD causes (eg, DME, RVO, 
ocular histoplasmosis, trauma) as assessed by FA and confirmed by central reading 
center. (This criterion is not applicable for fellow eye, in case of subjects who have 
only one eye or the fellow eye optical media opacity prevents from taking the 
FA/OCT/FP images and the fellow eye fulfills additional criteria specified in  Section 
8.3.4). 
7. Active or recent (within 28 days prior to Randomization) intraocular, extraocular, and 
periocular inflammation or infection in either eye. 
8. History of idiopathic or autoimmune-associated uveitis in either eye. 
9. Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
10. Unmedicated intraocular pressure (IOP) ≥ 30 mm Hg at Screening in either eye. 
11. Topical ocular corticosteroids administered for ≥ 30 consecutive days in the study eye 
within 90 days prior to Screening. 
12. Spherical equivalent of the refractive error in the study eye demonstrating more than 
8 diopters of myopia. 
13. Corneal transplant or corneal dystrophy in the study eye. 
14. History of rhegmatogenous retinal detachment in the study eye. 
15. History of macular hole in the study eye. 
16. Retinal pigment epithelial tear or rip involving the macula in the study eye as assessed 
by FA and confirmed by the central reading center. 
17. Current vitreous hemorrhage in the study eye. 
18. Subretinal hemorrhage that is ≥ 50% of the total lesion area in the study eye, or if the 
subretinal hemorrhage involves the fovea is 1 or more DA (≥ 2.54 mm2) in size in the 
study eye, as assessed by FA and confirmed by the central reading center. 

 
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19. Other intraocular surgery (including cataract surgery) in the study eye within the 
3 months prior to Baseline. The yttrium aluminum garnet [YAG] posterior 
capsulotomy is allowed no later than 4 weeks prior to Screening. 
20. Any concurrent intraocular condition in the study eye (eg, cataract or diabetic 
retinopathy) that, in the opinion of the investigator, could require treatment during the 
study period to prevent or treat loss of visual acuity.  
21. Significant media opacities (including cataract) in the study eye interfering with 
BCVA assessment or fundus imaging (FA/FP/OCT). 
22. Aphakia or absence of the posterior capsule in the study eye, unless it occurred as a 
result of a YAG posterior capsulotomy in association with prior posterior chamber 
intraocular lens (IOL) implantation. 
23. Presence of advanced glaucoma or optic neuropathy that involves or threatens the 
central visual field in the study eye (as judged by the investigator). 
24. History of glaucoma filtering surgery or ALT in the study eye (Exception: Laser 
iridotomy and SLT are allowed).  
25. Uncontrolled ocular glaucoma or hypertension in the study eye, defined as IOP ≥ 25 
mm Hg despite treatment with anti-glaucoma medication. 
26. Any previous systemic anti-VEGF treatment (eg, bevacizumab). 
27. Contraindication for Lucentis® (hypersensitivity to ranibizumab or to any of the study 
treatment excipients).  
28. Current treatment for active systemic infection. 
29. Females who are pregnant, nursing, planning a pregnancy during the study, or of 
childbearing potential and not using a reliable method of contraception (see 
Appendix 17.1) and/or not willing to use a reliable method of contraception during 
their participation in the study. A pregnancy test administered to women of 
childbearing potential at the Screening Visit (prior to treatment) must be negative 
for the patient to receive study medication. 
30. Participation in another clinical trial within the previous 3 months or any other clinical 
trial of anti-angiogenic drugs. 
31. Reasonable suspicion of other disease or condition that might render the subject at a 
high risk of treatment complications or otherwise confound interpretation of the study 
results (as judged by the investigator). 
32. PK subgroup only: Contraindication for additional blood sampling (as judged by the 
investigator). 
 

 
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8.3.4 Optic media opacity in one eye (fellow eye) 
There may be circumstances where subjects with only one eye or with the fellow eye 
with opaque optical media preventing from obtaining FA/OCT/FP images, could be 
considered for study participation. In those cases it is required that:  the subject  fulfills 
all study eligibility criteria; fellow eye suffers from visual impairment of BCVA less 
than 20/200 Snellen equivalent ( <50 ETDRS letters); the fellow eye has a known 
medical history leading to visual impairment; the fellow eye is not expected to be 
treated during study in any way and the inclusion of the subject in the study is approved 
by the study Medical Monitor. It must be noted that in such cases the images from the 
fellow may not be obtained due to optical media opacity, and therefore they do not need 
to be graded by the central imaging center.    
8.3.5 Removal of Subjects From Therapy or Assessments 
Subjects may stop study drug for any of the following reasons: 
• Subject request (ie, withdrawal of consent) 
• Use of nonpermitted concurrent therapy 
• Noncompliance with the study drug or study schedule 
• Lost to follow-up (defined as at least 2 missed study visits without any medical 
reason and without any contact with the study subject, despite the documented 
investigator’s efforts)  
• Occurrence of adverse events (AEs) not compatible with the continuation of 
subject participation in the study, in the investigator’s opinion, or unacceptable 
to the subject to continue 
• Investigator request 
• Intercurrent illness 
• Sponsor request 
• Treatment failure, as assessed by the treating investigator 
Subjects are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment. The reason(s) for withdrawal will 
be documented in the electronic case report form (eCRF). 
Subjects withdrawing from the study will be encouraged to complete the same final 
evaluations (ie, End of Treatment/ Week 52) as subjects completing the study according 
to this protocol, particularly safety evaluations. The aim is to record data in the same 
way as for subjects who completed the study. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These 
efforts must be documented in the subject’s file.  
The Sponsor has the right to terminate the study at any time in case of serious adverse 
events (SAEs) or if special circumstances concerning the study drug or the company 

 
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itself occur, making further treatment of subjects impossible. In this event, the 
investigator will be informed of the reason for study termination.  
Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the 
study, in subjects or female partners of male subjects, should be immediately confirmed 
and reported to the investigator, who will then withdraw the pregnant female subject 
from the study without delay. Subjects should also immediately notify investigators of 
any pregnancy occurring during the study but which was confirmed only after 
completion of the study. In the event that a subject is subsequently found to be pregnant 
after inclusion in the study, any pregnancy will be followed to term, and the status of 
mother and child will be reported to the Sponsor after delivery. 
Full details will be recorded on the withdrawal page of the eCRF, or an SAE report will 
be completed if the subject has completed the study. Details of the procedures to be 
followed if a pregnancy occurs are provided in Section 10.1.4.2.1.  
8.4 
Study Medications 
In this study, Xlucane 0.5 mg (0.05 mL of 10 mg/mL ranibizumab) will be administered 
by ophthalmic IVT injection (only) once every 4 weeks (approximately 28 days/ 
monthly) in the study eye for 12 months in subjects with wAMD who are randomized to 
receive Xlucane. 
Lucentis® 0.5 mg (0.05 mL of 10 mg/mL ranibizumab) will also be administered by 
ophthalmic IVT injection (only) once every 4 weeks (approximately 28 days/monthly) 
in the study eye for 12 months in subjects with wAMD who are randomized to receive 
Lucentis®.  
The study medication  (Xlucane & Lucentis®, respectively) should be administered only 
by qualified ophthalmologists experienced in IVT injections. 
 
The IVT injection procedure should be carried out under controlled aseptic conditions, 
which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or 
equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given 
prior to the injection. 
Approximately 30 minutes following the IVT injection, subjects should also be 
monitored for elevation in IOP using Goldmann tonometry. Noncontact tonometry is 
allowed but if IOP is greater than 30 mm Hg, the result should be confirmed by 
applanation tonometry (eg, Goldmann, Tonopen, Icare) within the next 30 minutes. 
Subjects should also be monitored onsite for (at least 60 minutes) and instructed to 
report any symptoms suggestive of endophthalmitis without delay following the 
injection. 

 
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Each vial should only be used for the treatment of a single eye (ie, the study eye). 
Lucentis® prefilled syringes may be used if needed (eg, if vials are not available). 
8.4.1 Identity of Study Medication  
Based on the design of this protocol, the Principal Investigator (PI) MUST oversee 
proper separation and delegation of unmasked study roles and responsibilities. To 
ensure the masking of each randomized subject, the PI must delegate tasks to an 
unmasked treating investigator and ample unmasked support staff to execute protocol 
instructions. 
Xlucane/ Lucentis® for IVT injection is supplied as single-use vial designed to deliver 
0.05 mL of 10 mg/mL ranibizumab. (Lucentis® prefilled syringes may be used if needed 
[eg, if vials are not available].) The details of the study medications are given in Table 
3. All study drug will be imported according to the relevant regulatory requirements. It 
must be noted that EU-Lucentis® is not FDA approved and is therefore considered an 
investigational new drug in the United States. 
 
Table 3 Study Medication Details 
Study 
Medication 
Dosage Form and Strength 
Manufacturer 
Xlucane 
Supplied as single-use, 2-cc glass vial 
containing 
2.3 
mg 
of 
proposed 
ranibizumab biosimilar in 0.23 mL 
solution designed to deliver 0.05 mL of 
10 mg/mL proposed ranibizumab 
biosimilar, by intravitreal injection. 
Xbrane Biopharma 
Retzius väg 8 
SE-171 65 Solna 
Sweden  
EU-licensed 
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. 
Novartis Pharma Stein AG 
Schaffhauserstrasse  
4332 Stein  
Switzerland 
 
8.4.1.1 Xlucane 
Xlucane is a sterile, colorless solution in a single-use glass vial. Xlucane is supplied as a 
sterile solution in a single-use container designed to deliver a 0.05 mg mL of 10 mg/mL 
ranibizumab.  
Xlucane is for IVT injection only. Keep vial(s) refrigerated at 2º-8ºC (36º-46ºF). Do not 
freeze. Protect vial(s) from direct sunlight.  

 
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There are no human- or animal-derived materials used in the Xlucane DS and Xlucane 
DP manufacturing process. A Master Cell Bank (MCB) has also been established for the 
DS manufacturing process.   
8.4.1.2 Lucentis® (ranibizumab injection) 
Xbrane has made a thorough physiochemical assessment, of Lucentis® to provide 
information for defining the quality target product profile. The choice of analytical 
methods is based on FDA Guidance, the EMA guideline, ICH Q5E, advice from the 
CHMP, and data available in the public domain for the reference product.5,15,16,17 
The quality target product profile (QTPP), has been determined by analysis and 
characterization of Lucentis® lots (SL732 expiry date 09-2019; ST601 expiry date 
11-2019; SR124 expiry date 01-2020; 3179575 expiry date 01-2020; SJ836 expiry date 
06-2019; SK351 expiry date 08-2019; SX444 expiry date 08-2020; and B0014801 
expiry date 08-2020). The QTPP is continuously updated with data from sourced and 
analyzed Lucentis® batches and it will serve as a basis for similarity evaluation of 
Xlucane GMP batches (manufactured for the phase III clinical study) to Lucentis®.  
Lucentis® is a sterile, colorless to pale yellow solution in a single-use prefilled syringe 
or a single-use glass vial. Lucentis® is supplied as a preservative-free, sterile solution in 
a single-use container designed to deliver 0.05 mL of 10 mg/mL Lucentis® (0.5 mg dose 
prefilled syringe or vial) aqueous solution with 10 mM histidine HCl, 10% α,α-trehalose 
dihydrate, 0.01% polysorbate 20, pH 5.5. 
Lucentis® should be refrigerated at 2º-8ºC (36º-46ºF). DO NOT FREEZE. Do not use 
beyond the date stamped on the label. Protect Lucentis® prefilled syringes and vials 
from light and store in the original container until time of use. Do not open Lucentis® 
prefilled syringe sealed tray until time of use. 
 
8.4.2 Packaging and Labeling 
All investigational products provided by the Sponsor are supplied as individual kits. 
Study medication will be packaged and labeled at a central packaging facility. All 
packaging and labeling operations will be performed according to Good Manufacturing 
Practice for Medicinal Products and the relevant regulatory requirements. 
Each study kit (1x white cartons) will contain either one 2-cc glass vial of Xlucane or one 
2-cc glass vial of Lucentis®. The Xlucane and Lucentis® single-use containers will be 
appropriately labeled. A clinical label will be placed on cartons and rendered tamper 
evident. Each kit will have unique identification number. 
Sites are to dispense the appropriate kit per IWRS information upon subject 
randomization and at each subsequent visit. Each study kit will have appropriate labeling 
information according to regulatory requirements. 

 
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Site must contact the CRA in case of any questions. 
The study medication kits must 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 until the time 
of use. Do Not Freeze. Do not use beyond the expiry date which is stated on the 
carton/vial. Do not use any kit if it is damaged. Study medication vials should be used 
once only and any unused portion left in the vials/syringes should not be considered for 
use. 
In case prefilled syringes are used as a contingency, additional documentation will be 
provided to investigators/sites and regulatory authorities as needed in compliance with 
country regulatory requirements. 

 
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8.4.3 Randomization 
The receipt and review of the lab report is necessary before randomizing a subject. 
Upon confirmation of eligibility for a given subject to participate in the study, a unique 
randomization number for that subject will be assigned via an IWRS. The IWRS will be 
accessed immediately by study site personnel after confirmation of the subject’s 
eligibility has been recorded. The randomization number for a given subject will be 
used to identify the study drug that will be administered to that subject.   
 
The randomization scheme will automatically ensure that the study drug assignment for 
a given subject is random and that an overall 1:1 ratio of assignments to each of the 2 
study drug treatments is approximated.   
 
In addition, the randomization scheme will include the following stratification 
parameters to ensure balanced distribution of assignment to the 2 treatments: eye color 
(light iris vs dark iris), geographical region where enrolled and the BCVA letters at 
Baseline (55 or lower, 56 to 65, 66 or higher). Permuted random blocks within each 
stratification combination will be used to ensure the 1:1 ratio within each combination.  
 
An independent biostatistician will create the randomization scheme, which will remain 
unavailable to all other masked individuals, until after study completion and subsequent 
locking of the study database.   
 
Once a randomization number has been assigned, that number must not be used again 
for any other subject (eg, when a subject is withdrawn from the study, that subject’s 
randomization number must not be used again for any other subject). 
 
8.4.4 Selection of Doses in the Study 
The dose and route of administration for Xlucane will be identical to that of Lucentis®. 
The recommended dose for Lucentis® is 0.5 mg (0.05 mL of 10 mg/mL ranibizumab) 
given as a single IVT injection every 4 weeks/monthly.  
 
8.4.5 Selection and Timing of Dose for Each Subject 
Subjects will be randomized by IWRS to receive 13 doses of either Xlucane or 
Lucentis® in the study eye, once every 4 weeks/monthly over 52 weeks. Proper aseptic 
injection technique should always be used when administering the IVT injections. 
The minimum interval between 2 consecutive injections/doses should not be less than 4 
weeks minus the visit window interval of the scheduled visit. 

 
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For example, Visit 3 (Week 2) to Visit 5 (Week 8) allow -2 day window, therefore the 
minimum interval between two consecutive injections between these visits can be 26 
days. 
Visit 6 (Week 12)  to Visit 16 (Week 52) allow a -5 day window, therefore the 
minimum interval between two consecutive injections between these visits can be 23 
days.  
If a visit is outside the protocol defined visit window, should be considered as ‘Late 
Visit or Out Of Window visit’ and must be entered in the CRF as a protocol deviation 
(PD). Visits that are delayed for more than 14 days from the scheduled visit date, should 
be considered as ‘missed’ visits. The next visit should be scheduled in consideration of 
the protocol defined interval as much as possible and as per medical judgement of the 
investigator. 
The study is expected to complete no later than one year or 12 months (+7 days) from 
the date of the last patient randomized into the study. This will be considered as the 
study end date and will be communicated once the last patient has been randomized. 
Patient visits should be scheduled as per the protocol and within stipulated visit 
windows to ensure all patients complete the study and have the EOT (Visit 16) 
scheduled within the study end date.  
If due to any reason it is not possible to complete all remaining visits for any patient 
within the study end date, an early termination visit must be scheduled and EOT 
procedures completed as per Section 8.1.1 
8.4.6 Masking 
Due to the study objectives, the identity of the study treatment assignments will not be 
known to subjects. Additionally, except for the site designees who are unmasked for the 
purpose of preparing and administering the study treatments, other research staff will 
also be masked. Masked study team members will perform efficacy assessments. 
There will be no overlap between the masked and unmasked staff members. Access to 
the randomization codes will be strictly controlled. 
The study medications will have caps/stoppers of differing colors and length; however, 
they will be packaged and labeled in identical outer cartons. Therefore, sites must have 
the following unmasked team members and their designated back-ups:  
• 
Unmasked personnel to prepare syringes for IVT injection and provide to the 
unmasked injector, and complete study drug accountability. 
• 
Unmasked injector to perform injection and safety assessments immediately after 
the injections (but not to participate in the efficacy assessments). 

 
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• 
There will also be masked and unmasked clinical research associates (CRAs) 
available for the same site. Unmasked CRAs will monitor study drug accountability.  
Randomization information for any particular subject may be made available to the 
investigator only in the event of a medical emergency or an AE that necessitates 
identification of the study drug for the welfare of that participant. Masking codes should 
only be broken in emergency situations for reasons of participant safety. Whenever 
possible, the investigator(s) should always consult with the medical monitor and the 
Sponsor prior to breaking the masking. 
When the masking code is broken, the reason must be fully documented. The reporting 
requirements for unmasking are the same for reporting an SAE. See also Section 
10.1.4.2.1 Serious Adverse Events.  
When all subjects have completed their 6-month assessments, an unmasked analysis of 
efficacy (ie, equivalence) and safety endpoints as well as PK and immunogenicity will 
be performed. The aim of the unmasked analysis is to initiate the submission of the 
application for marketing authorization as agreed with the European Medicines Agency. 
This analysis will not affect the further conduct of the study. 
8.4.7 Prior and Concomitant Therapy 
The use of any concurrent medication, prescription or over-the-counter, is to be 
recorded on the subject’s source document and corresponding electronic data capture 
form (eg, eCRF) along with the reason the medication was taken.  
Drug interaction studies have not been conducted with Lucentis®. 
 
During the study, subjects may not receive any standard or investigational agents for 
treatment of their AMD in the study eye other than study treatment until they have 
completed the final or early termination visit assessments. This includes medications 
administered locally (eg, IVT by juxtascleral or periorbital routes), as well as those 
administered systemically with the intent of treating the fellow eye. Vitamins and 
dietary supplements are allowed. 
In case the fellow eye develops AMD or other medical condition during the study, it is 
expected that the fellow eye may be treated locally (eg, IVT by juxtascleral or 
periorbital routes), with standard of care therapy per local clinical practice first.  
If anti-VEGF therapy is necessary, it is recommended to start it no earlier than after the 
last PK assessment and to perform the fellow eye IVT procedures in the interval 
between the study drug injections.  

 
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Any other medications that are considered necessary for the subject’s welfare and that 
are not expected to interfere with the evaluation of the study medication may be given at 
the discretion of the Investigator, with the exceptions noted below:  
• Any systemic treatment or ocular treatment with an investigational agent  
• Systemic anti-VEGF therapy  
 
If the permissibility of any medication/treatment is in question, please contact the 
medical monitor. Ocular surgery to the study eye should be delayed until the subject 
completes the study, if possible and safe. 
8.4.7.1 Rescue Medication 
No rescue treatment is allowed. Any subject who is in need of rescue treatment, in the 
judgement of the Principal Investigator, may be removed from the study. Early 
termination procedures will be completed as per Section 8.1.1. 
8.4.8 Known Contraindications 
8.4.8.1 Ocular or Periocular Infections 
Lucentis® is contraindicated in patients with ocular or periocular infections. 
8.4.8.2 Hypersensitivity 
Lucentis® is contraindicated in patients with known hypersensitivity to ranibizumab or 
any of the excipients in Lucentis®. Hypersensitivity reactions may manifest as severe 
intraocular inflammation. 
8.4.9 Warnings and Precautions 
Subjects should be monitored prior to and following each injection (for at least 
60 minutes) to permit any early treatment and appropriate management if needed.  
8.4.9.1 Endophthalmitis and Retinal Detachments 
IVT injections, including those with Lucentis®, have been associated with 
endophthalmitis and retinal detachments. Proper aseptic injection technique should 
always be used when administering study medication. In addition, patients should be 
monitored following the injection to permit early treatment should an infection occur. 
Subjects should also be advised that in the days following study medication 
administration, they are at risk of developing endophthalmitis. If the eye becomes red, 
sensitive to light, painful, or develops a change in vision, advise the subject to seek 
immediate care from the local investigator (ie, an ophthalmologist). 

 
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8.4.9.2 Increases in Intraocular Pressure 
Increases in IOP have been noted both before and after injection (at 60 minutes) while 
being treated with Lucentis®. Monitor IOP prior to and following IVT injection with 
study medication and manage appropriately. 
8.4.9.3 Thromboembolic Events 
Although there was a low rate of arterial thromboembolic events (ATEs) observed in 
the Lucentis® clinical trials, there is a potential risk of ATEs following IVT use of 
VEGF inhibitors. Arterial thromboembolic events are defined as nonfatal stroke, 
nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). 
The ATE rate in the 3 controlled wAMD studies (AMD-1, AMD-2, and AMD-3) during 
the first year was 1.9% (17 of 874) in the combined group of patients treated with 
0.3 mg or 0.5 mg Lucentis® compared with 1.1% (5 of 441) in patients from the control 
arms. In the second year of studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 
721) in the combined group of Lucentis®-treated patients compared with 2.9% (10 of 
344) in patients from the control arms. In study AMD-4, the ATE rates observed in the 
0.5 mg arms during the first and second year were similar to rates observed in studies 
AMD-1, AMD-2, and AMD-3.  
In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of 
Lucentis® used adjunctively with verteporfin photodynamic therapy [PDT), the stroke 
rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients 
treated with 0.5 mg Lucentis® compared to 1.1% (5 of 435) in patients in the control 
arms (odds ratio: 2.2 [95% CI: 0.8,7.1]). 
 
8.4.10 Treatment Compliance 
All study drug doses will be administered by trained staff at study centers.  
As study drug is administered in the clinic, treatment compliance will be overseen and 
documented by the investigator and study staff using the treatment records (and drug 
accountability records). At a minimum, date, time, and dose should be accurately 
recorded in real-time to confirm that each dose of study treatment was administered per 
the protocol. 
9 
TIMING OF STUDY PROCEDURES 
The planned study assessments are in Section 8.1.1 and 8.1.2. 
The BCVA will be quantified using the ETDRS method. The BCVA assessment will be 
performed by qualified study personnel following manifest refraction and precede any 
examination requiring contact with the study eye.  

 
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It is recommended that IOP is measured prior to pupil dilation as the IOP values may be 
influenced by the pupil dilation. Also the elevated IOP may alert the investigator that 
the pupil should not be dilated and additional examinations may have to be undertaken. 
Every effort should be made to have IOP measurements performed at approximately the 
same time of day and using the same type of instrument for a given subject throughout 
the study, whenever possible. For the pre-injection IOP measurements have to be 
performed using the Goldmann tonometry method. 
In case the sequence of procedures is different at any site due to their local SOPs, and 
IOP measurement is not performed as above, then the process should be kept the same 
for all study subjects at the site. However even in such cases the protocol requirement of 
IOP measurement using Goldmann applanation tonometer and prior to injection 
procedure must be followed. 
It also recommended that at the visits where both IOP measurement and FA is 
performed- IOP measurement is done first followed by fluorescein angiography test. 
It is expected that between IOP measurement and FA test photographs taken, there 
should be adequate time to wash-out all topical fluorescein.  
Subjects should be monitored onsite prior to and following each injection (for at least 
60 minutes) to permit any early treatment and appropriate management if needed. 
Investigators may use their clinical judgement to determine if any additional IOP 
lowering medications or any unscheduled assessments may be needed during the study. 
Subjects should also be advised that in the days following study medication 
administration, they are at risk of developing endophthalmitis. If the eye becomes red, 
sensitive to light, painful, or develops a change in vision, advise the subject to seek 
immediate care from the study doctor or an ophthalmologist. 
9.1 
Pre-treatment 
9.1.1 Screening Visit (Visit 1) 
• Subjects will provide written informed consent before any study-related 
procedures may be performed. 
• Assess for eligibility (against the inclusion and exclusion criteria). 
• Collect full medical history, historical disease data, diagnostic information, and 
concomitant illnesses/diseases, adverse events (including Baseline events), and 
concomitant medications. 
• Record demographic data, such as ethnic origin, date of birth, and sex. 
• Perform a physical examination (PE), including body mass index (height and 
weight measured). A PE will consist of a routine evaluation of organ systems 
(including head, ears, eyes, nose, throat, neck, cardiovascular, pulmonary, 
abdomen, skin, extremities, neurological, lymph nodes, and musculoskeletal).  

 
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o At the Screening Visit, the PE will include the collection of the subject’s 
eye color (ie, light iris or dark iris). 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform FA and OCT in both eyes, in which results should be submitted to and 
confirmed by the central reading center prior to Randomization. 
• Perform CFP in both eyes. 
• Perform SLE of the anterior segment in both eyes. 
• Perform dilated fundus examination of the posterior segment in both eyes. 
• Measure IOP in both eyes. Goldmann tonometry should be used for pre-injection 
IOP.   
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests. 
• For females of childbearing potential only, collect urine sample for pregnancy 
test. 
• Record any Baseline events and concomitant medications.  
 
9.2 
Treatment Period 
9.2.1 Day 0 Visit (Visit 2) - Baseline 
The Day 0 Visit (Visit 2) will take place after the Screening Visit (Visit 1). The 
following procedures will be performed before injection: 
• Reassess/confirm eligibility against the inclusion and exclusion criteria. 
• Confirm receipt of the central reading center’s interpretation(s) of FA and OCT 
from Screening. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction.  
• Perform SLE of the anterior segment in both eyes. 
• Perform dilated fundus examination of the posterior segment in both eyes. 
• Measure IOP in both eyes, using the Goldmann tonometry method. 
• Perform OCT in both eyes. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
• PK subgroup only: Collect additional blood sample(s) for PK evaluations ≤ 60 
minutes before the first dose.  
• Record any changes in adverse events and concomitant medications. 

 
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• Randomization will take place for eligible subjects, and each will receive a subject 
number. The receipt and review of the lab report is necessary before 
randomizing a subject. 
 
When all the above Day 0 (Visit 2) procedures have been performed/confirmed, the 
study drug will be administered as an IVT injection to the subject in the study eye only. 
The following shall be performed after injection: 
• Monitor the subject (after injection) for at least 60 minutes.  
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 36 mm Hg, 
it is recommended to perform another IOP measurement with Goldmann or 
Tonopen or ICare (applanation tonometer) within the next 30 minutes. 
• Record any AEs, including any ISRs. 
 
9.2.1.1 Day 1 (Visit 2b) for PK subgroup ONLY 
Only for the PK subgroup of subjects who agree to additional PK evaluations. At 23 
hours (± 60 minutes) after the first dose, subgroup subjects will be asked to return to the 
site for the following:  
• Record any changes in adverse events and concomitant medications. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. Non-contact 
tonometry may be used, but in the event IOP is greater than 36 mm Hg, it is 
recommended to perform another IOP measurement with Goldmann or Tonopen 
or ICare (applanation tonometer) within the next 30 minutes. 
• Adverse event reporting, if any.  
• Additional blood sample(s) to be collected for PK evaluations. 
9.2.2 Week 2/ Visit 3 (± 2 days) 
The Week 2 Visit will take place 14 days/ 2 weeks (± 2 days) after Visit 2. The 
following procedures will be performed:  
• Record any changes in adverse events and concomitant medications. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction.  
• Perform OCT in the study eye. 
• Record any AEs. 
 

 
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9.2.3 Week 4/ Visit 4 (± 2 days) 
The Week 4 Visit will take place 14 days/ 2 weeks (± 2 days) after Visit 3. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 
30 minutes. 
• Monitor the subject for any signs or symptoms at least 60 minutes after 
the injection. 
• Record any AEs, including any ISRs. 
 
9.2.4 Week 8/ Visit 5 (± 2 days) 
The Week 8 Visit will take place 28 days/ 4 weeks (± 2 days) after Visit 4. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 

 
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• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests.  
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 
30 minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs. 
 
9.2.5 Week 12/ Visit 6 (± 5 days) 
The Week 12 Visit will take place 28 days/ 4 weeks (± 5 days) after Visit 5. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 

 
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Goldmann, Tonopen or ICare (applanation tonometer) within the next 30 
minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs. 
 
9.2.6 Week 16/ Visit 7 (± 5 days) 
The Week 16 Visit will take place 28 days/ 4 weeks (± 5 days) after Visit 6. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• For subjects with any prior or present signs of intraocular inflammation: 
Collect blood sample(s) for immunogenic evaluations.  
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 
30 minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs. 
 
9.2.7 Week 20/ Visit 8 (± 5 days) 
The Week 20 Visit will take place 28 days/ 4 weeks (± 5 days) after Visit 7. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 

 
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• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 30 
minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs. 
 
9.2.7.1 Week 20 (Visit 8b) for PK subgroup ONLY 
Only for the PK subgroup of subjects who agree to additional PK evaluations. At 23 
hours (± 60 minutes) after the Visit 8 dose, subgroup subjects will be asked to return to 
the site for the following:  
• Record any changes in adverse events and concomitant medications. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. Non-contact 
tonometry may be used, but in the event IOP is greater than 36 mm Hg, it is 
recommended to perform another IOP measurement with Goldmann or Tonopen 
or ICare (applanation tonometer) within the next 30 minutes. 
• Adverse event reporting, if any.  
• Additional blood sample(s) to be collected for PK evaluations. 
 
9.2.8 Week 24/ Visit 9 (± 5 days) 
The Week 24 Visit will take place 28 days/ 4 weeks (± 5 days) after Visit 8. The 
following procedures will be performed before injection: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform FA (images of both eyes should be sent to CRC, grading of study eye 
only will be done by CRC) 

 
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• Perform OCT in the study eye. 
• Perform CFP in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed:  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 30 
minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs.   
 
9.2.9 Week 28 to Week 48 (every 28 days or every 4 weeks; monthly) [Visits 10 to 
15] (± 5 days) 
The monthly (ie, every 28 days or every 4 weeks) Week 28 to Week 48 Visits (Visits 10 
to 15) will take place 28 days/ 4 weeks (± 5 days) after the prior visit(s). The following 
procedures will be performed before injection at each visit: 
• Record any AEs and any changes in concomitant medication. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform OCT in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Measure IOP in the study eye by Goldmann tonometry method. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• For Week 36 (Visit 12) ONLY: Collect blood sample for hematology and 
clinical chemistry tests. Collect blood sample(s) for immunogenic (ie, anti-
ranibizumab antibodies and NAb) evaluations. 

 
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• For subjects with any prior or present signs of intraocular inflammation: 
Collect additional blood sample(s) for immunogenic evaluations.  
 
When all of these procedures have been performed, the study drug will be administered. 
Immediately, after the injection, the following shall be performed (at each visit):  
 
• Measure IOP in the study eye. After IVT injection (eg, 30 minutes post injection), 
non-contact tonometry may be used, but in the event IOP is greater than 
36 mm Hg, it is recommended to perform another IOP measurement with 
Goldmann or Tonopen or ICare (applanation tonometer) within the next 
30 minutes. 
• Monitor the subject for at least 60 minutes after the injection. 
• Record any AEs, including any ISRs. 
 
9.2.10 Week 52/ End-of-treatment or Early Withdrawal Visit/ Visit 16 (± 5 days) 
The End-of-treatment Visit (Week 52/ Visit 16) will take place 28 days (± 5 days) after 
the last injection of study drug or at the time of early discontinuation/withdrawal (if 
applicable). The following procedures will be performed: 
• Record any AEs and any changes in concomitant medication since the previous 
visit. 
• Perform a PE. A PE will consist of a routine evaluation of organ systems 
(including head, ears, eyes, nose, throat, neck, cardiovascular, pulmonary, 
abdomen, skin, extremities, neurological, lymph nodes, and musculoskeletal). At 
the Week 52/End of Treatment Visit, the PE will also include a query of the 
patient to determine if changes in his/her physical condition have occurred since 
the PE at Screening. 
• Perform BCVA assessment using the ETDRS at 4 meters, including manifest 
refraction. 
• Perform FA(images of both eyes should be sent to CRC, grading of study eye 
only will be done by CRC). 
•  Perform  OCT in the study eye. 
• Perform CFP in the study eye. 
• Perform SLE of the anterior segment in the study eye. 
• Perform dilated fundus examination of the posterior segment in the study eye. 
• Record vital signs including blood pressure and heart rate. Systolic and diastolic 
blood pressure and pulse rate will be measured after patients have been at rest 
(seated) for at least 5 minutes. 
• Collect blood sample for hematology and clinical chemistry tests. 
• Collect blood sample(s) for immunogenic (ie, anti-ranibizumab antibodies and 
NAb) evaluations. 

 
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• For females of childbearing potential only, collect urine sample for pregnancy 
test. 
• Measure IOP in both eyes, using the Goldmann tonometry method. In the event 
IOP is greater than 36 mm Hg, it is recommended to perform another IOP 
measurement with Goldmann or Tonopen or ICare (applanation tonometer). 
 
9.3 
Duration of Treatment 
The duration of treatment will be approximately 52 weeks, including follow-up. Pre-
treatment screening assessments shall occur within 21 days before the start of treatment.   
10 EFFICACY, PHARMACOKINETICS, IMMUNOGENICITY, AND SAFETY 
VARIABLES   
The planned schedule of assessments is in Section 8.1.1. The planned schedule of 
correlative assessments is in Section 8.1.2. 
10.1 Efficacy, Pharmacokinetics, Immunogenicity, and Safety Measurements 
Assessed  
10.1.1 Efficacy Variables  
The following methods will be used for assessing and recording efficacy.    
10.1.1.1 Best Corrected Visual Acuity Assessment 
• BCVA will be assessed at all visits by ETDRS and the following:  
o Mean change in BCVA 
o Percentage of subjects who lose <15 letters 
o Percentage of subjects who gain ≥15 letters 
10.1.1.2 Central Foveal Thickness   
• CFT will be assessed at all visits by OCT. 
10.1.1.3 Morphological Changes in the Neovascular Membrane 
• Changes in the size and/or number of intraretinal cystoid space (cysts), subretinal 
fluid, and retinal pigment epithelium detachments measured by qualitative 
morphology-based OCT data (in the study eye). 
10.1.1.4 Choroidal Neovascularization 
• Leakage and size from the choroidal neovascularization. 

 
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10.1.2 Pharmacokinetic Variables  
10.1.2.1 Pharmacokinetic Assessment(s) 
• One or more PK variables based on plasma concentration of ranibizumab (primarily 
expected Cmax). 
10.1.3 Immunogenicity Variables 
• Immunogenicity (ie, anti-ranibizumab antibodies and NAb) 
10.1.4 Safety Variables  
10.1.4.1 Safety Assessments 
• AEs, as detailed in the following section 
• ISRs (including endophthalmitis, vitritis, and haemorrhage) 
• Hematology and clinical chemistry (including analysis of alanine aminotransferase 
also known as serum glutamic-pyruvic transaminase [ALT/SGPT] and aspartate 
aminotransferase also known as serum glutamic-oxaloacetic transaminase 
[AST/SGOT] and creatinine) as detailed in the following section. 
10.1.4.2 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not it is related to the 
medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction, or the significant worsening 
of the indication under investigation that is not recorded elsewhere in the eCRF under 
specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, 
including the disease under study, that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the 
study. AEs will be elicited by asking the subject a nonleading question, for example, 
“Have you experienced any new or changed symptoms since we last asked/since your 
last visit?” AEs should be reported on the appropriate page of the eCRF. 

 
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Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort, 
and does not interfere with everyday activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, 
to the study drug. Causality should be assessed using the categories presented in the 
following table: 
Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the 
study drug. 
Related: 
Clinical event with plausible time relationship to study drug 
administration, and that cannot be explained by concurrent disease or 
other drugs or chemicals. 
Action Taken  
The investigator will describe the action taken with the study treatment in the 
appropriate section of the eCRF, as follows: 
• Dose not changed 
• Study drug permanently withdrawn 
• Study drug temporarily interrupted 
• Not applicable 
• Unknown 
 
Other Specific Treatment of Adverse Events 
The investigator will describe the other treatment(s) for the AE/SAE in the appropriate 
section of the eCRF, as follows: 
• None 
• Concomitant medication 

 
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• Other, specify. 
Follow-up of Adverse Events 
All investigators should follow up with subjects with AEs until the event is resolved or 
until, in the opinion of the investigator, the event is stabilized or determined to be 
chronic. Details of AE resolution must be documented in the eCRF. 
Subjects should be followed up for 28 days (± 5 days) after receiving the last dose of 
study drug, and any AEs that occur during this time should be reported according to the 
procedures outlined above. 
Documentation and Reporting of Adverse Events 
AEs should be reported and documented in accordance with the procedures outlined 
below. All AEs occurring during the study (from the time of receiving written informed 
consent to 28 days [± 5 days] of receiving last dose of study drug) must be documented 
on the relevant eCRF pages. The following data should be documented for each AE: 
• Description of the symptom event 
• Classification of “serious” or “not serious” 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken 
• Causal relationship 
• Outcome of event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported]) 
10.1.4.2.1 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of 
death from the event as it occurred, ie, it does not include a reaction that might 
have caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and [are] SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing 
non-worsening condition is not, however, considered an AE. The details of such 
hospitalizations must be recorded on the medical history or PE page of the 
eCRF). 

 
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• Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
subject’s ability to carry out normal life functions). 
• Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above. This may include any 
event that the investigator regards as serious that did not strictly meet the criteria above 
but may have jeopardized the subject or required intervention to prevent one of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the investigational 
product. 
Reporting of Serious Adverse Events 
Any SAE must be reported by the investigator if it occurs during the clinical study, from 
the time of receiving written informed consent to 28 days (± 5 days) of receiving last 
dose of study drug, whether or not the SAE is considered to be related to the 
investigational product. All SAEs must be reported by the investigator within 24 hours 
of becoming aware of the SAE. An SAE report consists of the SAE form, the medical 
history form, and the concomitant medication form. A copy of these forms must be sent 
within 24 hours of becoming aware to the attention of the product safety scientist at: 
Fax No.: 001-877-464-7787 
e-mail: SafetyReporting@SyneosHealth.com 
The investigator should not wait to receive additional information to document fully the 
event before notification of an SAE, though additional information may be requested. 
Where applicable, information from relevant laboratory results, hospital case records, 
and autopsy reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as 
to influence the overall assessment of safety, if brought to the attention of the 
investigator at any time after cessation of study drug administration and linked by the 
investigator to this study, should be reported to the study monitor. 
The Sponsor and/or Syneos Health will promptly notify all relevant investigators and 
the regulatory authorities of findings that could adversely affect the safety of subjects or 
the conduct of the study or alter the independent ethics committee (IEC)/institutional 
review board (IRB) approval/favorable opinion of the study. In addition, Syneos Health, 
on behalf of the Sponsor, will expedite the reporting to all concerned investigators, to 
the IECs/IRBs, where required, and to the regulatory authorities of all adverse reactions 
that are both serious and unexpected. 
Details of the procedures to be followed if a pregnancy occurs are provided as follows.  

 
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Pregnancy Reporting 
Pregnancies occurring in female subjects and female partners of male subjects during 
the study (from the time of first dose of study drug to 3 months after the last dose of 
study drug) should be reported by the investigator using the Pregnancy Report Form via 
email and fax (Section 10.1.4.2.1) immediately or within 24 hours of acknowledgement. 
The investigator will (1) notify the subject’s physician that the subject was being treated 
with an investigational drug (Xlucane) or approved control (Lucentis®/ranibizumab) and 
(2) follow the progress of the pregnancy. The investigator must document the outcome 
of the pregnancy and provide a copy of the documentation to the Sponsor. 
If a female partner of a male study subject becomes pregnant during the study, the 
investigator will also notify the Sponsor immediately after the pregnancy is confirmed. 
The investigator will (1) obtain a consent from the female partner for pregnancy follow-
up and (2) follow the progress of the pregnancy to term. The investigator should 
document the outcome of the pregnancy and provide a copy of the documentation to 
the Sponsor. 
Any pregnancy will be followed to term and the status of mother and child will also be 
reported to the Sponsor after delivery. Newborns should be followed up for at least 
30 days for any potential congenital anomalies. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Spontaneous abortions should always be reported as SAEs. 
10.1.4.2.2 Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the 
applicable product information (eg, investigator’s brochure for an unauthorized 
investigational medicinal product or summary of product characteristics for an 
authorized product). 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of 
expedited reporting. The Sponsor and/or Syneos Health shall ensure that all relevant 
information about a SUSAR that is fatal or life-threatening is reported to the relevant 
competent authorities and IEC/IRB within 7 days after knowledge by the Sponsor of 
such a case and that relevant follow-up information is communicated within an 
additional 8 days. All other SUSARs will be reported to the relevant competent 
authorities and IEC/IRB within 15 days after knowledge by the Sponsor of such a case. 
All investigators should follow up SUSARs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized or determined to be chronic. Post 

 
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study SUSARs that occur after the subject has completed the clinical study must be 
reported by the investigator to the Sponsor. 
10.1.4.2.3 Clinical Laboratory Evaluation 
The hematology and clinical chemistry laboratory analyses will be performed at a 
central laboratory (Q2 Solutions). Reference ranges will be supplied and used by the 
investigator to assess the laboratory data for clinical significance and pathological 
changes. The following laboratory safety tests will be performed at Screening, during 
treatment, and at the end of treatment. Results from Screening visit must be reviewed 
by the investigator before patient is randomized. 
Hematology 
The following will be evaluated: hemoglobin, hematocrit, white blood cell (WBC) 
count (total and differential), red blood cell (RBC) count, platelet count, mean cell 
volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin 
concentration (MCHC). 
Clinical Chemistry 
The following will be evaluated: creatinine, AST/SGOT, ALT/SGPT, alkaline 
phosphatase, lactate dehydrogenase (LDH), total bilirubin, albumin, total protein, 
sodium, potassium, chloride, glucose, uric acid, total cholesterol, triglycerides, calcium, 
and phosphorus. 
10.1.4.2.4 Other Laboratory Variables 
Screening for pregnancy will be performed (urine beta-human chorionic gonadotropin 
[β-HCG]) at Screening, for females only. Kits will be provided by the central 
laboratory. 
Blood samples will be collected for PK and immunogenic (ie, anti-ranibizumab 
antibodies and NAb) testing, at Baseline, during treatment and, at the end of treatment; 
PK and immunogenicity assessments will be done by Syneos Health laboratory. 
10.1.4.2.5 Vital Signs 
Vital signs (blood pressure and heart rate) will be recorded at Screening, during 
treatment (except Week 2 [Visit 3]), and at the end of treatment in a standardized 
manner. Systolic and diastolic blood pressure and pulse rate will be measured after 
patients have been at rest (seated) for at least 5 minutes. 

 
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10.1.4.2.6 Ophthalmological Examination 
At Screening, during treatment, and at the end of treatment, an ophthalmological 
examination will be performed. Any changes from Screening to end of treatment/study 
will be recorded. 
IOP measurements will be conducted at all visits (except Visit 3 [Week 2]). 
10.1.4.2.7 Other Safety Assessments  
A PE will be performed at Screening (with body mass index) and at the End of 
Treatment/Early Termination Visit. A PE will consist of a routine evaluation of organ 
systems (including head, ears, eyes, nose, throat, neck, cardiovascular, pulmonary, 
abdomen, skin, extremities, neurological, lymph nodes, and musculoskeletal). At the 
Week 52/End of Treatment Visit, the PE will also include a query of the patient to 
determine if changes in his/her physical condition have occurred since the PE at 
Screening.  
10.1.5 Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and 
generally recognized as reliable, accurate, and relevant to the disease condition. 
10.1.6 Drug Concentration Measurements  
The plasma levels of ranibizumab will be evaluated at Baseline, on Day 1 at 23 hours 
(± 60 minutes) after the first dose, and at steady-state at Week 20 at 23 hours 
(± 60 minutes) after the sixth dose to detect any notable differences in systemic 
exposure between the 2 products, Xlucane and Lucentis®. The assay will be developed 
with sufficient sensitivity to be able to detect the differences at such low plasma levels. 
10.2 Stopping Rules 
The estimated duration of the study is contingent on safety and the number of injections 
evaluated. The study will be stopped in the event of any new findings that indicate a 
relevant deterioration of the risk-benefit relationship that would render continuation of 
the study unjustifiable. Study treatment will be halted, and the appropriate individuals 
from the Sponsor and Syneos Health will determine if the study should be terminated 
for any safety concerns.  
The Sponsor may also end the study for administrative reasons.  
Should the study be terminated prematurely, the Sponsor will provide written 
notification to all investigators and regulatory authorities specifying the reason(s) for 
early termination. The investigator must inform the Independent Ethics Committees 

 
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(IECs)/Institutional Review Board (IRB) promptly and provide the reason(s) for the 
termination. Previously dosed subjects will be assessed through all planned study visits.  
11 STATISTICAL METHODS 
11.1 General Considerations 
Before unmasking the data for subjects included in this trial for the interim analysis, a 
statistical analysis plan (SAP), which will provide the technical details of the statistical 
analyses outlined here, will be prepared, finalized, and signed.   
In general, data will be summarized by means of summary statistics. Continuous data 
will be presented as the number of observations, mean, standard deviation (SD), 
minimum, Q1, median, Q3, and maximum. Categorical data will be presented as counts 
and percentages. The data will be presented for each treatment group by visit. All data 
summarized will be presented in patient listings. 
11.2 Analysis Sets 
The Enrolled Set will consist of all patients enrolled in the study, ie, all patients who 
signed the informed consent form. This set will be used for summaries of disposition for 
all patients enrolled. 
The Full Analysis Set (FAS) will include all patients for whom treatment regimen has 
been assigned. The FAS will be used for all analyses of efficacy endpoints. Patients will 
be analyzed according to the randomized treatment. Different strategies will be applied 
for handling data following intercurrent events (IE) (see Section 11.3.3.1). Unless stated 
otherwise, all subject listings will be presented using this set. 
The Safety Set (SS) will include all patients who receive at least 1 dose of study drug. 
Patients will be analyzed according to treatment received. The SS will be used for 
analyses of safety endpoints. 
 
The Pharmacokinetic Set (PKS) will include patients in the SS who have at least 1 
postdose evaluable plasma ranibizumab concentration value. Patients will be analyzed 
according to treatment received. For cases in which a PD is identified to potentially 
affect plasma level, the identified concentration values will be flagged as non-evaluable 
and excluded from the analyses. 
  
A blinded data review meeting (BDRM) will be held prior to database lock and 
unblinding of the interim analysis to agree upon the PKS, PK samples/parameters to be 
included in the analyses, and any data to be excluded from the FAS analyses due to IEs. 
All patients for whom data were impacted due to the COVID-19 pandemic will be 
identified as well as the data points affected. Such data will be recorded as a protocol 
deviation and will be assessed at the BDRM along with all other PDs with respect to 

 
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potential to affect the efficacy results. Attendees will include appropriate individuals 
from the Sponsor and Syneos Health. Details regarding the data to be reviewed at the 
meeting will be documented in the SAP and a separate BDRM plan.  
 
11.3 Planned Analyses 
11.3.1 Patient Disposition 
Screen failures (with reasons), randomization, and dosing with study drug will be 
summarized for the Enrolled Set.  
Study completion and early termination (with reasons) as well as attendance at each 
visit will be summarized for the FAS.   
Inclusion in each analysis set will be summarized, along with reasons for exclusion.   
11.3.2 Demographic and Other Baseline Characteristics 
Demographics and key baseline characteristics will be summarized. 
11.3.3 Efficacy Endpoints 
11.3.3.1 Primary Efficacy Endpoint 
The primary endpoint of the study is the change in BCVA letters at Week 8 compared to 
Baseline using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol for 
the study eye. 
 
Due to the increase in protocol deviations related to the COVID-19 pandemic and 
following the recent ICH E9 (R1) Addendum19, the primary and secondary estimands of 
the study related to efficacy are detailed in this section. These estimands were not 
explicitly defined in earlier versions of the protocol (see Section 18) but the estimand 
framework provides a more comprehensive approach to show the impact of Covid-19 in 
the analysis20. The presence of such IEs in a biosimilarity study may introduce potential 
bias and a dilution of treatment differences (i.e. increasing the chance of proving 
equivalence), as such the ordering of the estimands described below (in terms of 
primary and secondary) are chosen.  
For the primary estimand, the scientific question of interest is the between-group 
difference (Xlucane v Lucentis®) in the mean change from baseline in BCVA letter 
score at Week 8 in patients who fulfil the study eligibility criteria, have no IEs up to and 
including the Week 8 BCVA assessment and complete 8 weeks of treatment of study 
drug (given as a single ophthalmic IVT injection every 4 weeks/monthly). 
 
IEs are defined as: 

 
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• 
Early discontinuation of study treatment. Subsequent missing data (missing or 
collected) will be imputed in the analysis with a hypothetical strategy. 
• 
Non-adherence with the protocol which would potentially affect the efficacy results. 
Such identified data at the BDRM (missing or collected) will be imputed in the 
analysis with a hypothetical strategy. 
• 
Start of anti-VEGF treatment in the fellow eye. Subsequent data (missing or 
collected) will be imputed in the analysis with a hypothetical strategy. 
  
The secondary estimand of the study for the primary endpoint will use alternate 
methods of handling data following IEs compared to the primary estimand. This 
approach will use a treatment policy with respect to IEs such that any data collected 
following the IE will be used in the analysis. So the scientific question of interest is the 
between-group difference (Xlucane v Lucentis®) in the mean change from baseline in 
BCVA letter score at Week 8 in patients who fulfil the study eligibility criteria and 
complete 8 weeks of treatment of study drug, regardless of any other IEs. However, 
because the study design does not plan for assessments following early treatment 
discontinuation, a true treatment policy strategy is not possible to apply. As such, any 
missing data following early treatment discontinuation will be imputed using a 
hypothetical strategy.  
Assumptions for imputing missing data due to IEs and analysis methods for each 
estimand are detailed in Section 11.3.7. 
 
The change in BCVA letters at Week 8 compared to Baseline using the ETDRS 
protocol will be analyzed using a mixed model for repeated measures (MMRM). An 
MMRM approach will be fitted with geographical region of the country where enrolled, 
visit, eye color (light iris vs dark iris), treatment, and treatment-by-visit interaction as 
fixed effects, with the baseline BCVA letters and baseline BCVA letters-by-visit 
interaction as covariates. The treatment differences from the model at Week 8 will be 
evaluated and a 95% or 90% two-sided CI for the least squares mean difference between 
groups will be calculated. To prove the 2 products to be biosimilar, the confidence 
limits for this difference have to be within the equivalence margin of ± 3.5 letters for the 
primary estimand. The secondary estimand analysis will be supportive of the primary 
estimand analysis. 
 
11.3.3.2 Secondary Efficacy Endpoints 
The same properties of the primary and secondary estimand of the primary endpoint will 
be considered for each of the secondary endpoints. For responder analyses, the between-
group difference in proportions (Xlucane v Lucentis®) will be of interest.   
The following continuous secondary endpoints will be analyzed in a similar fashion to 
the primary efficacy endpoint: 

 
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• Change in BCVA letters at Week 4, Week 12, Week 16, Week 24, Week 36 and Week 
52 compared to Baseline using the ETDRS protocol 
• Change in total size of choroidal neovascular leakage area in the study eye measured 
by FA at Week 24 and Week 52 compared to Baseline 
• Change in total size of choroidal neovascularization in the study eye measured by FA 
at Week 24 and Week 52 compared to Baseline 
• Change in Central Foveal Thickness (CFT) in the study eye measured by OCT at 
Week 2, Week 4, Week 8,Week 16, Week 24, Week 36 and Week 52 compared to 
Baseline 
• Changes in the size and/or number of intraretinal cystoid space (cysts), subretinal 
fluid, and retinal pigment epithelium detachments in the study eye measured by 
qualitative morphology-based OCT 
The following secondary endpoints will be analysed (stratified by randomization 
stratification group) using a Cochran-Mantel-Haenzel test and Miettinen-Nurminen 
methods to obtain the difference in proportions between groups and corresponding 90% 
and 95% CIs.  
• Percentage of subjects with loss of <15 letters using ETDRS, evaluated as change at 
Week 4, Week 8, Week 24, and Week 52 compared to Baseline in the study eye 
• Percentage of subjects with gain of ≥15 letters using ETDRS, evaluated as change at 
Week 4, Week 8, Week 24, and Week 52 compared to Baseline in the study eye 
• Percentage of subjects without intra- or subretinal fluid in the study eye (ie, 
completely dry) at Week 24 and Week 52 
• Percentage of subjects with retinal pigment epithelium detachments in the study eye 
 
11.3.4 Safety Endpoints 
11.3.4.1 Adverse Events 
Events that occur after a patient provides informed consent but before the time of the 
first dose of study drug will be considered non-treatment-emergent adverse events 
(AEs). Treatment-emergent AEs (TEAEs) are defined as events that are newly 
occurring or worsening from the time of the first dose of study drug.   
Reported AE terms will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms and system organ classes (SOCs).   
The percentage of patients with TEAEs together with the number of the respective 
TEAEs overall, by SOC, and by preferred terms within each SOC will be presented. 
Separate summaries will be provided for overall TEAEs, TEAEs by severity, 

 
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treatment-related TEAEs, serious TEAEs, and TEAEs leading to treatment 
discontinuation.   
All AEs will be presented in patient listings. 
11.3.4.2 Other Safety Endpoints 
The following endpoints (as well as the change from Baseline when applicable) will be 
summarized: 
• Injection site reactions 
• Vital signs (heart rate, systolic blood pressure, diastolic blood pressure) 
• Clinical chemistry (creatinine, AST/SGOT, ALT/SGPT, alkaline phosphatase, 
lactate dehydrogenase (LDH), total bilirubin, albumin, total protein, sodium, 
potassium, chloride, glucose, uric acid, total cholesterol, triglycerides, calcium, 
and phosphorus) 
• Immunogenicity (ie, anti-ranibizumab antibodies and NAb)  
11.3.5 Pharmacokinetics 
The PK data analysis will be performed using the PK Set. 
The ranibizumab PK concentrations will be summarised by treatment and listed 
individually. Descriptive statistics on the PK parameters (C0, predose; C1, time point 23 
hours [± 60 minutes] after the first dose on Day 1; and C6, time point 23 hours [± 60 
minutes] after the sixth dose on Week 20) will be presented.  If a difference in 
ranibizumab protein concentration between Xlucane and Lucentis® batches is detected, 
additional descriptive statistics will be presented taking such difference into account. 
Further details will be defined in the statistical analysis plan. 
11.3.6 Interim Analyses 
When all subjects have completed their 6-month assessments, an unmasked analysis of 
efficacy and safety endpoints as well as PK and immunogenicity will be performed. The 
aim of the unmasked analysis is to initiate the submission of the application for 
marketing authorization as agreed with the European Medicines Agency. This analysis 
will not affect the further conduct of the study. 
 
11.3.7 Handling of Missing Data 
Any data following an IE, which is deemed to have been impacted by the IE, may be 
treated as missing data in the analysis in accordance with Section 11.3.3.1.  

 
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For the primary analysis of each endpoint/estimand, a missing at random (MAR) 
approach will be assumed for missing data (ie, the probability of an observation being 
missing depends only on observed measurements). Sensitivity analyses will be 
conducted using different missing data assumptions such as missing not at random 
(MNAR) and missing completely at random (MCAR) within each endpoint/estimand.  
For continuous endpoints, a MMRM model will be used (using only evaluable data) to 
adopt a MAR assumption for the primary analysis. Patients with missing data at a 
particular time point still contribute to the analysis at that time point based on their other 
observed data used in the MMRM (ie, visit, treatment, baseline BCVA letter score, 
geographical region of the country where enrolled, eye color (light iris vs dark iris), and 
BCVA letter score at other visits) and the known covariance structures between these 
factors. The sensitivity analyses will use alternate methods (to be detailed in the SAP) 
of imputing missing data such as multiple imputation with pattern mixture modelling 
and using evaluable data only. ANCOVA models will be used to analyze such data at 
the respective visit. 
For non-continuous endpoints, alternate methods will be specified in the SAP to impute 
missing data, although the same mechanisms will be assumed as for continuous 
endpoints (ie, primary analysis assumes MAR, sensitivity analyses to assess MNAR and 
MCAR). 
Due to the indication under evaluation in this study, it is considered that most missing 
data due to COVID-19 can be treated as MAR, but this will be evaluated and agreed at 
the BDRM. Additional subgroup and sensitivity analyses relating to the potential bias 
from missing data and/or deviations from the protocol during the COVID-19 pandemic 
will be considered for analysis of all endpoints and added to the SAP prior to database 
lock. 
11.4 Determination of Sample Size 
The change in BCVA after 8 weeks was evaluated from previous studies based on 
similar patient populations. There was a wide range of SD across the studies, ranging 
from 8.58 letters to 11.83 letters. 
For the purpose of sample size calculation, an SD of 10 letters will be assumed for this 
study. This is based on an analysis of the data from clinical trials of the originator 
product demonstrating a clear correlation between baseline BCVA and the SD of the 
change of BCVA at Week 8. Considering that a narrower inclusion criterion for BCVA 
is being applied in this study compared to the studies of the originator product, it is 
expected that a baseline BCVA of around 60 letters will be observed. Therefore, an SD 
of 10 for the primary endpoint is well in the upper range of what is expected. 

 
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From 580 randomized patients there will be >90% power to show equivalence (ie, two-
sided 95% CI for the mean difference between Xlucane and Lucentis® is confined 
within the equivalence margin of ± 3.5 letters) if the SD is no more than 10. 
 
The power calculations were performed using SAS® (Version 9.3, SAS Institute Inc., 
Cary, NC, USA). 
 
11.5 Protocol Deviations 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the 
study, subject management, or subject assessment will be identified, evaluated, and 
closed prior to the respective database lock (interim or final analysis) and will be 
described in the final SAP/clinical study report. 
 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit 
during the course of the study by the Sponsor or its nominated representative. In 
addition, inspections may be conducted by regulatory authorities at their discretion. 
12.2 Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed 
for each subject who signs an informed consent form (ICF) and is administered 
study drug. 
In accordance with current GCP and ICH guidelines, the study monitor will carry out 
source document verification at regular intervals to ensure that the data collected in the 
eCRF are accurate and reliable.  
The investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, 
and representatives from regulatory authorities direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of data contained 
within the eCRFs.   
12.3 Data Management and Coding 
Syneos Health will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 
generated within this clinical study will be handled according to the relevant standard 
operating procedures (SOPs) of the data management and biostatistics departments of 
Syneos Health. 

 
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Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must 
be verifiable against source documents at the study center. Data to be recorded directly 
on the eCRF will be identified and the eCRF will be considered the source document. 
Any changes to the data entered into the EDC system will be recorded in the audit trail 
and will be FDA CFR 21 Part 11 compliant. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and WHO Drug Dictionary for medications. 
Missing or inconsistent data will be queried in writing to the investigator for 
clarification. Subsequent modifications to the database will be documented. 
12.4 Quality Management and Risk Evaluation 
Details will be provided in a separate Integrated Quality Risk Management 
(IQRM) Plan. 

 
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13 RECORDS AND SUPPLIES 
13.1 Drug Accountability 
On receipt of the study drug, the investigator (or designee) will conduct an inventory of 
the supplies and verify that study drug supplies are received intact and in the correct 
amounts before completing a supplies receipt. The investigator will retain a copy of this 
receipt at the study center and return the original receipt to the unmasked study monitor. 
The unmasked monitor may check the study supplies at each study center at any time 
during the study. 
It is the responsibility of the unmasked study monitor to ensure that the investigator (or 
designee) has correctly documented the amount of study drug received, dispensed, and 
returned on the dispensing log that will be provided. A full drug accountability log will 
be maintained at the study center at all times. The study monitor will also perform an 
inventory of study drug at the close-out visit to the study center. All discrepancies must 
be accounted for and documented. 
13.2 Financing and Insurance 
Financing and insurance for this study will be outlined in a separate agreement between 
Syneos Health and the Sponsor. 

 
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14 ETHICS 
14.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the subjects, and any other relevant study documentation will be 
submitted to the appropriate IEC/IRB. Written approval of the study and all relevant 
study information must be obtained before the study center can be initiated or the study 
drug is released to the investigator. Any necessary extensions or renewals of IEC/IRB 
approval must be obtained for changes to the study such as amendments to the protocol, 
the ICF, or other study documentation. The written approval of the IEC/IRB together 
with the approved ICF must be filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the study. The investigator 
will submit written summaries of the study status to the IEC/IRB as required. On 
completion of the study, the IEC/IRB will be notified that the study has ended. 
14.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and 
approval before the beginning of the study. On completion of the study, the regulatory 
authorities will be notified that the study has ended. 
14.3 Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
14.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
The investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to 
participate in the study. 
The investigator or designated personnel will inform the subject of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the study. The 
subject should be given every opportunity to ask for clarification of any points that 
he/she does not understand and, if necessary, ask for more information. At the end of 
the interview, the subject will be given ample time to consider the study. Subjects will 
be required to sign and date the ICF. After signatures are obtained, the ICF will be kept 

 
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and archived by the investigator in the investigator’s study file. A signed and dated copy 
of the subject ICF will be provided to the subject or authorized representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw 
from the study at any time, without consequences for their further care or penalty or loss 
of benefits to which the subject is otherwise entitled. Subjects who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) 
(and regulatory authorities, if required). The study subjects will be informed about this 
new information and reconsent will be obtained. 
14.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the locally and/or nationally recognized 
authorities, as well as that of any other applicable agency(ies), will be granted direct 
access to the study subjects’ original medical records for verification of clinical study 
procedures and/or data, without violating the confidentiality of the subjects to the extent 
permitted by the law and regulations. In any presentations of the results of this study or 
in publications, the subjects’ identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be 
managed by the investigator and his/her staff with adequate precautions to ensure 
confidentiality of those data, and in accordance with any required authorizations, 
applicable to national and/or local laws and regulations on personal data protection. 

 
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15 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced. After completion of the study 
(end of study defined as the date of the last visit of the last subject), all documents and 
data relating to the study will be kept in an orderly manner by the investigator in a 
secure study file. This file will be available for inspection by the Sponsor or its 
representatives. Essential documents should be retained for 2 years after the final 
marketing approval in an ICH region or for at least 2 years since the discontinuation of 
clinical development of the investigational product. It is the responsibility of the 
Sponsor to inform the study center when these documents no longer need to be retained. 
The investigator must contact the Sponsor before destroying any study-related 
documentation. In addition, all subject medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical 
practice. 
The Sponsor must review and approve any results of the study or abstracts for 
professional meetings prepared by the investigator(s). Published data must not 
compromise the objectives of the study. Data from individual study centers in 
multicenter studies must not be published separately. 

 
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16 REFERENCES 
 
Schmidt-Erfurth U, Chong V, Loewenstein A, et al. Guidelines for the management 
of neovascular age-related macular degeneration by the European Society of Retina 
Specialists (EURETINA). Br J Ophthalmol. 2014;98(9):1144-1167.  
 
National Eye Institute [Internet]. Bethesda (MD): National Institutes of Health 
(US); Facts About Age-Related Macular Degeneration; reviewed 2018 May; 
cited 2018 May 31. Available from: https://nei.nih.gov/health/maculardegen/armd
_facts. 
 
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; Feb; 2(2):e106–16. 
 
Virgili G, Michelessi M, Parodi MB, et al. Laser treatment of drusen to prevent 
progression to advanced age-related macular degeneration. Cochrane Database Syst 
Rev. 2015; 10:CD006537. 
 
Lucentis: EPAR – Scientific Discussion [Internet]. European Medicines Agency. 
2007. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/
EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf. 
 
Chen Y, Wiesmann C, Fuh G, et al. Selection and analysis of an optimized anti-
VEGF antibody: crystal structure of an affinity-matured Fab in complex with 
antigen. J Mol Biol. 1999; Nov 5;293(4):865–81. 
 
Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, et al. 
VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure 
of the complex at 2.4 A resolution and mutational analysis of the interface. Struct 
Lond Engl 1993. 1998 Sep 15;6(9):1153–67. 
 
Lowe J, Araujo J, Yang J, et al. Ranibizumab inhibits multiple forms of biologically 
active vascular endothelial growth factor in vitro and in vivo. Exp Eye Res. 2007; 
Oct; 85(4):425–30. 
 
5701026 Main Report. In Vivo Study. Investigator's Brochure for Xlucane. Xbrane 
Biopharma; Forthcoming. 
 
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; 
MARINA Study Group. Ranibizumab for neovascular age-related macular 
degeneration. N Engl J Med. 2006;355(14):1419-31. 

 
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Food and Drug Administration (FDA) Guidance for Industry. Non-Inferiority 
Clinical Trials to Establish Effectiveness. U.S. Department of Health and Human 
Services. Center for Drug Evaluation and Research (CDER). Center for Biologics 
Evaluation and Research (CBER). November 2016. 
 
Potter MJ, Szabo SM, Li WW. Comparison of visual acuity outcomes in 
predominantly classic vs occult lesions in age-related macular degeneration treated 
with photodynamic therapy. Eye. 2008;22:194-99.  
 
Moseley J. Visual Function Endpoints The Regulatory Perspective. EMA Scientific 
Advice. EMA Ophthalmology Workshop. 2011. 
 
Markun S, Dishy A, Neuner-Jehle S, Rosemann T, Frei A. The Chronic Care for 
Wet Age Related Macular Degeneration (CHARMED) Study: A Randomized 
Controlled 
Trial. 
Virgili 
G, 
ed. PLoS 
ONE. 
2015;10(11):e0143085. 
doi:10.1371/journal.pone.0143085. 
 
EMA guideline on “Similar biological medicinal products containing monoclonal 
antibodies: non-clinical and clinical issues” (EMA/CHMP/BMWP/403543/2010). 
 
EMA Guideline on Similar Biological Medicinal Products (CHMP/437/04 Rev. 1). 
 
ICH Guideline on Comparability of Biotechnological/Biological Products Subject 
to Changes in Their Manufacturing Process Q5E (Step 4 version/ 18 November 
2004). 
 
Brown DM, Kaiser PK, Michels M et al. Ranibizumab versus Verteporfin for 
Neovascular Age-Related Macular Degeneration. N Engl J Med 2006;355:1432-44. 
 
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials (Date for coming into effect 30 
July 2020) 
 
Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials (Adopted by CHMP 26 June 2020) 

 
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17 APPENDICES 
17.1 Examples of Acceptable Contraception 
For females:  
a. Complete abstinence, defined as complete avoidance of heterosexual 
intercourse  
b. Bilateral tubal ligation or salpingectomy 
c. Partner underwent vasectomy 
d. Hormonal methods of contraception, including combined oral 
contraceptive pills, injectables, implants, and intrauterine devices (IUDs) 
e. Nonhormonal IUDs (ie, copper) 
f. Condom or occlusive cap (diaphragm, sponge, or cervical/vault caps) with 
spermicide combined with a hormonal method 
 
For males:  
a. Complete abstinence, defined as complete avoidance of heterosexual 
intercourse  
b. Bilateral orchiectomy 
c. Vasectomy 
d. Condom with spermicide if female partner uses a hormonal method 
  

 
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17.2 Investigator Signature Page 
Protocol Title: 
Xplore: A Phase III Double-Blind, Parallel Group, Multicenter Study to 
Compare the Efficacy and Safety of Xlucane versus Lucentis® in Patients 
with Neovascular Age-Related Macular Degeneration 
Protocol Number: 
XBR1001 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including 
appendices, and I will conduct the study as described in compliance with this protocol 
(and amendments), GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the independent ethics committee/institutional 
review board (IEC/IRB), I will not modify this protocol without obtaining prior 
approval of Xbrane Biopharma and of the IEC/IRB. I will submit the protocol 
amendments and/or any ICF modifications to Xbrane Biopharma and the IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to the Sponsor. Clinical information may be 
reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Xbrane Biopharma, to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
Investigator Signature 
Date 
Printed Name 
Institution 
 

 
Xbrane Biopharma   
 
24 Feb 2021                                      
XBR1001                                                            Amendment 5 Version 1 
Page 88 of 88                                      
 
 
CONFIDENTIAL 
18 PROTOCOL AMENDMENT SUMMARY OF CHANGES 
18.1 Summary of Changes 
Following is a summary of content-oriented changes that were made to each section of 
the protocol, and a brief rationale for these changes. Minor editorial and document 
formatting revisions have not been summarized. Key additions are in bold and 
underlined. 
 
Protocol Section 
 
Summary of Changes 
Rationale for Changes 
Title page 
Update of Sponsor address. 
Change of address.  
2 Study Personnel 
Updated contact details of 
Project Manager. 
Change of Project Manager. 
2 Other Personnel 
Physical address of central 
laboratory in North America has 
been specified. Telephone and 
fax number updated 
accordingly. 
Clarification. The central 
laboratory vendor in North 
America has not changed.  
3 Synopsis – Study 
design  
Clarification regarding the 
maintenance of blinding in 
connection to interim analysis.  
Text was added to clarify that 
subjects´treatment assignment 
will not be revealed in connection 
to Interim Analysis and thereby 
the blinding of the study will be 
maintained.  
8.4.2 Packaging and 
Labeling 
Central provision of BD needles 
and syringes is suspended until 
further notice. Should this 
change, the sites will be 
informed via an official letter.  
Company decision.