A Multi Center, Randomized, Double-Masked, Active-Controlled, Comparative Clinical Study to Evaluate the Efficacy and Safety of MYL-1701P and Eylea® in Subjects With Diabetic Macular Edema (DME)
Phase: PHASE3
Conditions: Diabetic Macular Edema
Sponsor: Mylan Pharmaceuticals Inc

MYL-1701P-3001 CLINICAL STUDY PROTOCOL 
Protocol Title 
A Multi Center, Randomized, Double-Masked, Active-Controlled, 
Comparative Clinical Study to Evaluate the Efficacy and Safety of 
MYL-1701P and Eylea® in Subjects with Diabetic Macular Edema 
Product 
MYL-1701P (M710) 
Protocol 
Number 
MYL-1701P-3001 
Study Type 
Comparative Safety and Efficacy 
Version 
Version 3.0 
Protocol Date 
09 Jun 2020 
Legal/Filing 
Sponsor 
Mylan 
  
  
 
Confidentiality: 
This protocol is the confidential, intellectual property of Mylan Inc. It should not be disclosed 
to a third party with the exception of regulatory agencies and study audit personnel that being 
Mylan employees, representatives, agents and/or contractors responsible for conducting the 
clinical study/trial, audits. Reproduction, modification, or adaption in part or in total is 
strictly forbidden without prior written approval by Mylan Inc./ Momenta Pharmaceuticals, 
Inc. 
Confidential
Page 2 of 517
ClinicalTrials.gov Identifier: NCT03610646

 
 
MYL-1701P-3001 
Page 2 of 79 
Version 3.0, Dated 09 Jun 2020 
Confidential 
SIGNATURE PAGE 
Protocol Description 
A Multi Center, Randomized, Double-Masked, 
Active-Controlled, Comparative Clinical Study to Evaluate 
the Efficacy and Safety of MYL-1701P and Eylea® in 
Subjects with Diabetic Macular Edema 
Product Code 
MYL-1701P 
Protocol Version  
Version 3.0 
Protocol Version Date
09 Jun 2020
I have read this protocol and affirm that the information contained herein is complete and 
accurate.  
 
 
 
Date: ______________________________         
 
 
 
Date: ______________________________         
 
 
 
Date: ______________________________         
 
 
 
Date: ______________________________         
 
 
 
 
Date: ______________________________         
Confidential
Page 3 of 517

PRINCIPAL INVESTIGATOR ACCEPTANCE FORM 
SIGNATURE OF INVESTIGATOR 
I, the undersigned, as Investigator for this study, have read this protocol numbered 
MYL-1701P-3001 and agree to conduct the study as outlined herein and in accordance with 
all applicable requirements of the country where the study is being conducted, the country 
where the study will be submitted, and the Sponsor’s requirements. Applicable guidelines and 
regulations include, but are not limited to: 
• Permission to allow the Sponsor and/or its agent or regulatory agencies to inspect 
study facilities and pertinent records at reasonable times and in a reasonable manner 
that ensures subject confidentiality. 
• Immediate notification of the Sponsor and/or its agent of any regulatory inspection 
related to this study. 
• Submission of the proposed clinical investigation, including the protocol and consent 
form, to a duly constituted IRB/Ethics Committee for approval, and acquisition of 
written approval for each, prior to study initiation. 
• Use of IRB/Ethics Committee-approved written informed consent that is obtained 
prior to study initiation for each subject.  
• Submission of any proposed change in or deviation from the protocol to the 
IRB/Ethics Committee using a signed formal amendment document prepared by the 
Sponsor and/or its agent.  Any proposed change(s) or deviation(s) from the protocol 
require that the informed consent also reflect such change(s) or deviation(s), and that 
the revised informed consent be approved by the IRB/Ethics Committee. 
• Documentation and explanation of the individual protocol deviations on the 
appropriate CRF page or other Sponsor-approved document. 
• Submission of written reports of serious AEs, as defined in the protocol, to the 
Sponsor within 24 hours. 
• Adherence to ICH GCP guidelines. 
 
 
Signature (Investigator) and Date 
…………………………………………………………………………………………………….. 
Name 
 
Contact Details 
 
 
Confidential
Page 4 of 517

CLINICAL STUDY CONTACT LIST 
Sponsor: 
Mylan 
  
,  
  
 
Sponsor GCRD Representative: 
 
 
 
 
 
 
 
Sponsor Statistical Representative: 
 
 
 
 
 
 
 
 
 
Sponsor GCO Representative: 
 
 
 
 
 
 
 
 
Sponsor Bioanalytical 
Representative: 
 
 
 
 
  
 
. 
 
Sponsor Safety Reporting Hotline: 
 
 
 
 
Confidential
Page 5 of 517

PROTOCOL SYNOPSIS 
Protocol Title 
A Multi Center, Randomized, Double-Masked, Active-Controlled, Comparative 
Clinical Study to Evaluate the Efficacy and Safety of MYL-1701P and Eylea® 
in Subjects with Diabetic Macular Edema 
Protocol 
Number 
MYL-1701P-3001 
Background 
and Rationale 
Diabetic retinopathy is an important cause of blindness worldwide. The 
International Diabetes Federation estimates that 285 million people worldwide 
have diabetes mellitus and that approximately 7% of these individuals are 
affected by diabetic macular edema. 
EYLEA® (aflibercept) injection, an anti-Vascular Endothelial Growth Factor 
(VEGF) agent, has been approved by the FDA and EMA for the treatment of 
Diabetic Macular Edema (DME). Eylea is being marketed by Regeneron 
Pharmaceuticals, Inc. in the US and Bayer AG in EU. 
Mylan Inc. and Momenta Pharmaceuticals, Inc. are developing MYL-1701P, a 
proposed biosimilar to Eylea, and this study will serve to demonstrate the 
clinical similarity of MYL-1701P and Eylea with regard to efficacy, safety, 
pharmacokinetics and immunogenicity in the treatment of patients with DME. 
Primary 
Objectives 
The primary objective is to demonstrate the clinical equivalence of MYL-
1701P and Eylea over 8 weeks of treatment at doses and regimen recommended 
by the Eylea US Prescribing Information, as assessed by change from baseline 
to week 8 in best corrected visual acuity (BCVA). 
Primary 
endpoints 
The primary efficacy endpoint will be the mean change from baseline in BCVA 
as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 
week 8. 
Methodology 
and treatments 
This is a multi-center, randomized, double-masked, active-controlled, 
comparative clinical study to demonstrate that no clinically meaningful 
differences exist between MYL-1701P and US-licensed Eylea in subjects with 
DME treated up to 52 weeks. 
Three hundred and twenty-four (324) eligible adult subjects with type 1 or 2 
diabetes mellitus with central DME involvement and BCVA between 73 and 38 
letters based on ETDRS letters (20/40 – 20/200 Snellen equivalent) in the study 
eye and central retinal thickness (CRT) ≥ 300 µm, as determined by spectral 
domain – optical coherence tomography (SD-OCT) in the study eye, will be 
randomized 1:1 to intravitreal treatment with MYL-1701P or Eylea. 
 
 
 
 
 Randomization will be stratified based on 
Baseline BCVA, i.e., ETDRS letter scores 73-55 vs. 54-38 and geographical 
region (US, EU, Japan and rest of the world). 
At study week 8, the primary endpoint will be assessed, and subjects will 
continue to receive the assigned treatment until Week 48. An end of study visit 
will be conducted at Week 52. Subjects will receive intravitreal injections of 
MYL-1701P or Eylea throughout the 52-week treatment period, with planned 
doses at Study Days 1, 29 (week 4), 57 (week 8), 85 (week 12), 113 (week 16), 
169 (week 24), 225 (week 32), 281 (week 40) and 337 (week 48). Additional 
doses may be administered at Week 20, Week 28, Week 36 and Week 44 based 
on the visual acuity, and/or SD-OCT as per the protocol specified criteria for 
administering additional 4-weekly doses.  
It should be noted that in most subjects where Eylea was dosed every 4-weeks 
Confidential
Page 6 of 517

compared to every 8 weeks, no additional efficacy was observed. Hence, it is 
expected that most of the subjects may not require additional 4-weekly doses. 
All subjects will return to clinic every 4 weeks for assessment of visual acuity 
(BCVA based on ETDRS letters) and central retinal thickness (CRT by 
SD-OCT) to assess efficacy and to guide treatment. There will be additional 
visits during the study as specified in the study schedule for safety and 
pharmacokinetic evaluation.  
 
 
 
 
Immunogenicity will be assessed for all the subjects participating in the study, 
through assessment of blood samples for anti-drug antibody and neutralizing 
antibody throughout the study. Along with immunogenicity, free aflibercept 
concentration in the blood samples from all subjects will be determined to 
evaluate drug tolerance status. 
Pharmacokinetic (PK) samples will be collected in patients identified for PK 
subpopulation (at least 32 in each study arm). Subjects in the PK subpopulation 
will have to visit the sites for 2 additional visits for sampling (visits V2 and 
V7A). 
Investigational 
Products 
Test product: MYL-1701P (a proposed biosimilar to Eylea) injection for 
intravitreal injection. 
Reference Product: Eylea for intravitreal injection, sourced from the United 
States. 
Inclusion/ 
exclusion 
criteria 
Inclusion criteria 
Each subject must meet all of the following criteria to participate in the study: 
1. Male or female subjects age ≥ 18 years. For Japan, in case of a subject 
under 20 years old, his/her legally acceptable representative should 
provide the informed consent for the study participation. 
2. Subjects have type 1 or type 2 diabetes mellitus who present with 
central DME involvement (defined as retinal thickening with a 
measurement of 300µm or more involving the 1 mm CRT by SD-OCT) 
in the study eye. 
3. The cause of decreased vision in the study eye has been attributed 
primarily to DME by the Investigator. 
4. Subjects must have BCVA at 4 m from 73 to 38 letters (ETDRS chart) 
equivalent to Snellen visual acuity of 20/40 to 20/200 in the study eye. 
5. Subject is able to understand and voluntarily provide written informed 
consent to participate in the study. 
6. If female of child bearing potential, the subject must have a negative 
serum pregnancy test at the Screening visit and a negative urine 
pregnancy test at baseline visit, and should not be nursing or planning a 
pregnancy. 
7. If female, subject must be: 
a. Surgically sterilized via hysterectomy, bilateral oophorectomy, 
or bilateral tubal ligation; or 
b. Of childbearing potential and practicing an acceptable form of 
birth control (defined as the use of an intrauterine device; a 
barrier method, like condom, with spermicide; any form of 
hormonal contraceptives; or abstinence from sexual 
intercourse) starting 60 days prior to dosing and continuing at 
Confidential
Page 7 of 517

least 90 days following the last treatment.  
c. Of non-childbearing potential (i.e., postmenopausal for at least 
1 year). 
For Japan: If female, subject must be 
• 
Of non-childbearing potential (i.e., surgically sterilized via 
hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation, or postmenopausal* for at least 1 year);  
* definition: she is not menstruating for at least 12 months 
without any other medical reason. 
• 
Of childbearing potential and practicing an acceptable form of 
birth control (defined as the use of an intrauterine device; a 
barrier method, like condom, with spermicide; any form of 
hormonal contraceptives; or abstinence from sexual 
intercourse) starting 60 days prior to dosing and continuing at 
least 90 days following the last treatment 
For Czech Republic: If female, must be permanently sterile or 
subject must be using a birth control method, which is considered 
as highly effective (described in detail in Section 4.4.2), starting 60 
days prior to dosing and continuing at least 90 days following the 
last treatment 
8. If male, subject must be surgically or biologically sterile. If not sterile, 
the subject must agree to use an acceptable form of birth control with 
sexual partner (as described in inclusion criteria #7b) or abstain from 
sexual relations during the study period and up to 90 days following the 
last treatment dose. 
For Czech Republic: If male, subjects should use highly effective 
method of contraception starting 60 days prior to dosing and continuing 
at least 90 days following the last treatment (described in detail in 
Section 4.4.3). 
9. Subject is willing to comply with the study duration, study visits and 
study related procedures. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the 
study: 
1. Subjects with known hypersensitivity to aflibercept or any of the 
excipients in MYL-1701P and Eylea 
2. Known hypersensitivity to fluorescein 
3. Ocular media of insufficient quality to obtain fundus and OCT images 
4. Subjects will be excluded if any of the following conditions are met in 
the study eye: 
a. Subjects with a history of vitreoretinal surgery in study eye 
and/or including scleral buckling 
b. Subjects who have had panretinal or macular laser 
photocoagulation within 3 months of randomization 
c. Subjects with history of use of intraocular corticosteroids 
anytime in the past or periocular (subconjunctival, intra-scleral, 
sub-tenon or retrobulbar) corticosteroids within 4 months of 
randomization 
d. Subjects who have reduced vision due to causes other than 
DME, with the exception of requirement for spherical 
correction, or mild cataract assessed by the Investigator as not 
Confidential
Page 8 of 517

interfering with assessment of BCVA or CRT 
e. Subjects with active proliferative diabetic retinopathy  
f. Subjects with active ocular inflammation 
g. Subjects who have had cataract or other intraocular surgery 
within 3 months of randomization or expected to undergo 
cataract surgery or capsulotomy during the study duration 
h. Subjects who have had laser capsulotomy within 3 months of 
randomization 
i. 
Subjects with aphakia, whether congenital or surgical 
j. 
Subjects with vitreous hemorrhage 
k. Subjects with visually significant vitreomacular traction or 
epiretinal membrane evident biomicroscopically or on OCT 
that is thought to affect central vision 
l. 
Subjects with myopia of spherical equivalent of ≥ - 8 diopters, 
prior to any possible refractive or cataract surgery 
m. Subjects with any other disease that might compromise visual 
acuity or require medical or surgical intervention during the 
study period, or could confound interpretation of the results 
(including retinal vascular occlusion, retinal detachment, 
macular hole or choroidal neovascularization of any cause) 
n. Structural damage to the center of the macula that is likely to 
preclude improvement in BCVA following the resolution of 
macular edema including atrophy of the retinal pigment 
epithelium, subretinal fibrosis or scar, significant macular 
ischemia or organized hard exudates based on the 
Investigator’s discretion with help of FA/FP and OCT. 
o. Subjects with uncontrolled glaucoma (defined as intraocular 
pressure ≥ 25 mmHg despite treatment with antiglaucoma 
medication); subjects with controlled glaucoma may participate 
in the study.  
For India, subjects with a clinical diagnosis of glaucoma 
(controlled or uncontrolled). 
p. Surgery for glaucoma in the past or likely to be needed in the 
future 
q. Intraocular pressure ≥25 mm of Hg in the study eye 
r. Prior treatment with verteporfin (photodynamic therapy) 
5. Subjects will be excluded if any of the following conditions are met in 
either eye: 
a) Subjects with active iris neovascularization 
b) Subjects with preretinal fibrosis involving the macula 
c) Subjects with history of idiopathic or autoimmune uveitis 
d) Subjects with active or suspected ocular or peri-ocular infection 
including but not limited to infectious blepharitis, keratitis, scleritis, or 
conjunctivitis 
6. Subjects who received previous therapy with antiangiogenic drugs for 
either eye (pegaptanib, bevacizumab, ranibizumab, aflibercept). 
7. Subjects who have received previous systemic antiangiogenic drugs 
(bevacizumab, aflibercept). 
8. Subjects with current or planned use of systemic medications known to 
be toxic to the lens, retina or optic nerve, including deferoxamine, 
chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
Confidential
Page 9 of 517

ethambutol. 
9. Subjects who plan to participate in another clinical study while enrolled 
in this study and/or who have received an investigational drug and/or 
device within 30 days or 5 half-lives, whichever is longer, prior to 
screening. 
10. Subject receiving treatment for a serious systemic infection. 
11. Subjects with uncontrolled diabetes mellitus as defined by HbA1c 
≥10% at screening 
12. Subjects with uncontrolled hypertension defined as systolic blood 
pressure > 160 mm Hg or diastolic blood pressure > 95 mm of Hg.  
13. Subjects with a history of cerebrovascular accident or myocardial 
infarction within 6 months of randomization. 
14. Subjects with renal failure requiring dialysis or renal transplant. 
15. Subjects who have only one functional eye, even if the eye met all 
other study requirements, or who have an ocular condition on the 
fellow eye with a poorer prognosis than the study eye. 
16. Presence or history of malignant neoplasm (including 
lymphoproliferative disease), except for adequately treated basal cell 
carcinoma and cervical carcinoma in situ; or any malignancy with 
complete remission of more than 5 years. 
17. Subjects with a history or presence of clinically significant 
cardiovascular, pulmonary, hepatic, renal, hematologic, 
gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 
oncologic, psychiatric disease, or any other condition, that in the 
opinion of the Investigator would jeopardize the safety of the subject or 
the validity of the study results. 
Sample size 
 
 
 
 A total of 324 subjects will be randomized at 1:1 
ratio to each arm after allowing for approximately 10% drop-outs. 
 
 
 
 
 
Statistical 
Methods 
For the primary endpoint of change from baseline in BCVA at Week 8, the 
primary analysis will be based on a mixed model repeated measures analysis 
with terms for treatment, visit, treatment by visit interaction, and region, 
together with baseline BCVA as a covariate.  
The within subject variance-covariance matrix will be assumed to be 
unstructured; estimation will use restricted maximum likelihood, and the 
denominator degrees of freedom will use the Kenward-Roger estimate. This 
model will provide an estimate, standard error, and 90% as well as 95% two-
sided CIs for the treatment difference at Week 8. If these CIs are fully 
contained within the interval (-3, 3) then equivalence will have been 
demonstrated.  
The primary analysis will be performed on the Full Analysis Set and will 
include data from all visits regardless of whether the subject is still receiving 
study medication.  
Additionally, sensitivity analysis of the primary endpoint will be conducted, in 
which BCVA values after discontinuing study medication will be excluded. 
Supportive analyses of the primary endpoint will also be produced based on the 
Confidential
Page 10 of 517

Per Protocol Population. 
Reporting 
Strategy 
 
 
 
 
  
Complete efficacy, safety, pharmacokinetics and immunogenicity data through 
Week 52 will be included in the 52-Week CSR. Study will continue to be 
double-masked until Week 52. 
 
Confidential
Page 11 of 517

TABLE OF CONTENTS 
CLINICAL STUDY CONTACT LIST ..................................................................................... 4 
PROTOCOL SYNOPSIS........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 11 
LIST OF COMMONLY USED ABBREVIATIONS.............................................................. 17 
1 
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES ............................. 19 
2 
INTRODUCTION ........................................................................................................... 23 
2.1 
Indication ................................................................................................................. 23 
2.2 
Background and Rationale ....................................................................................... 23 
2.2.1 Rationale for Study .............................................................................................. 23 
2.2.1.1 Rationale for Study Population- Diabetic Macular Edema ........................... 24 
2.2.1.2 Rationale for Subject Selection and Study Endpoints ................................... 24 
2.3 
Study Design ............................................................................................................ 25 
2.3.1 Pharmacokinetic Subpopulation .......................................................................... 26 
2.3.3 Reporting Strategy ............................................................................................... 26 
2.4 
Potential Risks ......................................................................................................... 26 
2.4.1 Safety Profile of Eylea ......................................................................................... 27 
2.4.2 Intravitreal injections ........................................................................................... 27 
2.4.3 Eye examination and Investigations .................................................................... 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 29 
3.1 
Objectives ................................................................................................................ 29 
3.1.1 Primary objective ................................................................................................. 29 
3.1.2 Secondary objectives ........................................................................................... 29 
3.2 
Endpoints ................................................................................................................. 29 
3.2.1 Primary Endpoints ............................................................................................... 29 
3.2.2 Secondary Endpoints ........................................................................................... 29 
3.2.2.1 Efficacy ......................................................................................................... 29 
3.2.2.2 Safety ............................................................................................................. 29 
3.2.2.3 Immunogenicity ............................................................................................ 30 
3.2.2.4 Pharmacokinetics .......................................................................................... 30 
4 
STUDY POPULATION .................................................................................................. 31 
4.1 
Study Population ...................................................................................................... 31 
4.2 
Sample Size Considerations ..................................................................................... 31 
4.3 
Inclusion and Exclusion Criteria .............................................................................. 31 
Confidential
Page 12 of 517

4.3.1 Inclusion Criteria ................................................................................................. 31 
4.3.2 Exclusion Criteria ................................................................................................ 32 
4.3.3 Criteria for study drug termination, withdrawal from the study and study 
termination ....................................................................................................................... 34 
4.4 
Contraception ........................................................................................................... 35 
4.4.1 Females - Non-Childbearing Potential................................................................. 35 
4.4.2 Females - Childbearing Potential ......................................................................... 35 
4.4.3 Male subjects (only for patients in Czech Republic) ........................................... 36 
4.5 
Pregnancy Testing .................................................................................................... 37 
5 
STUDY DRUG ................................................................................................................ 38 
5.1 
Investigational Drug ................................................................................................. 38 
5.1.1 Administration of Study Drugs ............................................................................ 38 
5.1.2 Criteria for administering additional 4-weekly doses .......................................... 38 
5.1.3 Delayed and Missed Visits and/or Dose .............................................................. 38 
5.1.4 Administration Procedure .................................................................................... 39 
5.2 
Drug Inventory ......................................................................................................... 39 
5.3 
Study Medication Complaints.................................................................................. 40 
5.4 
Storage, Disposition of Unused Study Drug and Drug Accountability ................... 40 
5.5 
Masking.................................................................................................................... 40 
5.6 
Randomization ......................................................................................................... 42 
5.7 
Breaking the Mask ................................................................................................... 42 
5.8 
Concomitant Medications ........................................................................................ 43 
5.8.1 Study Eye ............................................................................................................. 43 
5.8.2 Fellow / Non-study Eye ....................................................................................... 44 
5.8.3 Management of Diabetes ..................................................................................... 44 
6 
STUDY CONDUCT ........................................................................................................ 45 
6.1 
Screening Procedures ............................................................................................... 45 
6.1.1 Screening Visit [Day -28 to Day -1] .................................................................... 45 
6.2 
Treatment phase ....................................................................................................... 46 
6.2.1 Baseline Visit/Visit 1 (Day 1) .............................................................................. 46 
6.2.2 Visit 2 (Day 3) ..................................................................................................... 47 
6.2.3 Visit 3 (Week 1 ± 2 days) .................................................................................... 47 
6.2.4 Visit 4 (Week 4 ± 3 days) .................................................................................... 47 
6.2.5 Visit 5 (Week 8 ± 3 days) .................................................................................... 48 
6.2.6 Visit 6 (Week 12 ± 7 days) .................................................................................. 48 
Confidential
Page 13 of 517

6.2.7 Visit 7 (Week 16 ± 7 days) .................................................................................. 48 
6.2.8 Visit 8 (Week 20 ± 7 days)/ Visit 10 (Week 28 ± 7 days)/ Visit 12 (Week 36 ± 7 
days)/Visit 14 (Week 44 ± 7 days) .................................................................................. 49 
6.2.9 Visit 9 (Week 24 ± 7 days) .................................................................................. 49 
6.2.10 
Visit 11 (Week 32 ± 7 days) ............................................................................. 50 
6.2.11 
Visit 13 (Week 40 ± 7 days) ............................................................................. 50 
6.2.12 
Visit 15 (Week 48 ± 7 days) ............................................................................. 50 
6.2.13 
Visit 16 (Week 52 ± 7 days) [End of Study Visit] ........................................... 51 
6.2.14 
Early Termination (ET) visit ............................................................................ 51 
6.3 
Treatment Procedures .............................................................................................. 52 
6.3.1 Efficacy Assessments ........................................................................................... 52 
6.3.1.1 Ophthalmologic Examination ....................................................................... 52 
6.3.1.2 BCVA ............................................................................................................ 53 
6.3.1.3 SD-OCT/CRT................................................................................................ 53 
6.3.1.4 Fluorescein Angiography/ Fundus Photography ........................................... 54 
6.3.2 Safety Testing ...................................................................................................... 54 
6.3.2.1 Adverse Event Assessment ........................................................................... 54 
6.3.2.2 Laboratory Safety .......................................................................................... 54 
6.3.2.3 Vital Signs ..................................................................................................... 55 
6.3.2.4 12-lead ECG .................................................................................................. 56 
6.3.2.5 Targeted Physical Examination ..................................................................... 56 
6.3.3 Pharmacokinetic Assessment ............................................................................... 56 
6.3.4 Immunogenicity Assessment ............................................................................... 56 
6.3.5 Blood Volume ...................................................................................................... 57 
6.3.5.1 Immunogenicity Blood Sampling ................................................................. 57 
6.3.5.2 Pharmacokinetic Blood Sampling (CTAD Plasma) ...................................... 57 
6.3.5.3 Safety Blood Sampling.................................................................................. 57 
6.3.5.4 Shipment of Samples ..................................................................................... 57 
7 
STATISTICAL ANALYSIS ........................................................................................... 58 
7.1 
Sample Size Determination ...................................................................................... 58 
7.2 
Primary Endpoints ................................................................................................... 59 
7.2.1 Definition of Primary Endpoints .......................................................................... 59 
7.2.2 Statistical Methodology for Primary Endpoints .................................................. 59 
7.2.3 Primary Analysis for Primary Endpoints ............................................................. 59 
7.2.4 Sensitivity Analyses for Primary Endpoints ........................................................ 59 
Confidential
Page 14 of 517

7.2.5 Missing Data ........................................................................................................ 60 
7.2.6 Sub-Group Analyses ............................................................................................ 60 
7.3 
Secondary Endpoints ............................................................................................... 60 
7.3.1 Efficacy ................................................................................................................ 60 
7.3.2 Safety ................................................................................................................... 60 
7.3.3 Immunogenicity ................................................................................................... 61 
7.3.4 Pharmacokinetics ................................................................................................. 61 
7.4 
Analysis Set Definitions .......................................................................................... 61 
7.5 
Interim Analyses ...................................................................................................... 61 
7.6 
Other Safety Analyses .............................................................................................. 61 
7.6.1 Vital Signs ............................................................................................................ 61 
7.6.2 ECG Analyses ...................................................................................................... 61 
7.6.3 Laboratory Data ................................................................................................... 62 
8 
ADMINISTRATIVE PROCEDURES ............................................................................ 63 
8.1 
Source Documentation Forms.................................................................................. 63 
8.2 
Access to Data/Source Documentation .................................................................... 63 
8.3 
Clinical Study Report and Case Report Forms (CRFs) ........................................... 63 
8.4 
Adherence to Protocol.............................................................................................. 63 
8.5 
Data Handling and Record Retention ...................................................................... 64 
8.6 
Confidentiality ......................................................................................................... 64 
8.7 
Ethics and Regulatory Authorities ........................................................................... 64 
8.7.1 Institutional Review Board/Ethics Committee .................................................... 64 
8.7.2 Regulatory Authority ........................................................................................... 64 
8.8 
Informed Consent..................................................................................................... 65 
8.9 
Disclosure and Publication of Clinical Study Data .................................................. 65 
8.10 
End of Study ............................................................................................................ 65 
9 
ADVERSE EVENT REPORTING.................................................................................. 66 
9.1 
Adverse events ......................................................................................................... 66 
9.2 
Definitions................................................................................................................ 66 
9.2.1 Adverse Events .................................................................................................... 66 
9.2.2 Adverse Drug Reaction ........................................................................................ 66 
9.2.3 Unexpected Adverse Event/Adverse Drug Reaction ........................................... 67 
9.2.4 Serious Adverse Events ....................................................................................... 67 
9.3 
Management of Adverse Events .............................................................................. 68 
9.3.1 Collection ............................................................................................................. 68 
Confidential
Page 15 of 517

9.3.2 Evaluation ............................................................................................................ 69 
9.3.2.1 Severity Assessment of Adverse Events ....................................................... 69 
9.3.2.2 Action Taken ................................................................................................. 70 
9.3.2.3 Outcome at the Time of Last Observation .................................................... 70 
9.3.2.4 Causality Assessment of Adverse Events ..................................................... 70 
9.3.2.5 Documentation .............................................................................................. 71 
9.3.2.6 Treatment of Adverse Events ........................................................................ 72 
9.3.2.7 Follow-up ...................................................................................................... 72 
9.3.2.8 Notification .................................................................................................... 72 
9.3.2.9 Regulatory Reporting .................................................................................... 73 
9.4 
Special Situations ..................................................................................................... 73 
9.4.1 Pregnancy ............................................................................................................. 74 
9.4.2 Overdose, Medication Errors and Other Events .................................................. 74 
9.4.3 Worsening of diabetic macular edema ................................................................. 74 
9.5 
Abnormal Test Findings .......................................................................................... 74 
10 REFERENCE LIST ......................................................................................................... 76 
11 APPENDIX. ..................................................................................................................... 78 
11.1 
Appendix: NIAID / FAAN clinical criteria for diagnosis and assessment of 
Anaphylaxis (Sampson et al., 2006) .................................................................................... 78 
Confidential
Page 16 of 517

LIST OF TABLES 
Table 1: Study Schedule .......................................................................................................... 20 
Table 2: List of Prohibited Treatment ...................................................................................... 43 
Table 3: Laboratory Safety Tests ............................................................................................. 55 
Table 4: Change from Baseline in BCVA at Week 8 - VIVID and VISTA Studies ............... 58 
Table 5: Fixed Effects Meta-analysis of VIVID and VISTA Studies ..................................... 59 
Table 6: Clinical Severity of Adverse Events .......................................................................... 69 
Table 7: Action Taken for an Adverse Event .......................................................................... 70 
Table 8: Definition of Suspected Relationship between the Events and Study Medication .... 71 
 
LIST OF FIGURES 
Figure 1: Study Diagram .......................................................................................................... 19 
 
 
Confidential
Page 17 of 517

LIST OF COMMONLY USED ABBREVIATIONS 
AE 
Adverse event 
ADR 
Adverse drug reactions 
ALT 
Alanine transaminase 
AMD 
Age-related macular degeneration 
AST 
Aspartate transaminase 
BCVA  
Best corrected visual acuity 
BP 
Blood Pressure 
CI 
Confidence interval 
Cmax 
maximum plasma concentration 
COVID-19 
Corona virus disease - 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRT 
Central retinal thickness 
CSR 
Clinical Study Report 
CTAD 
Buffered citrate, theophylline, adenosine, and dipyridamole 
DME 
Diabetic Macular Edema 
ECG 
Electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EMA 
European Medicines Agency 
FA 
Fluorescein angiography 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Fundus photography 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent ethics committee 
IFU 
Instructions For Use 
IRB 
Institutional Review Board 
IOP 
Intraocular pressure 
IXRS 
Interactive response system 
kg 
kilogram 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeter of mercury 
MMRM 
Mixed Model Repeated Measures 
NIAID/ 
FAAN 
National Institute of Allergy and Infectious Disease and  
the Food Allergy and Anaphylaxis Network 
PI 
Prescribing Information 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PSRM 
Product safety and risk management 
QC 
Quality Control 
QTc 
QT corrected 
QTcF 
QT corrected (Fredericia’s correction) 
RVO 
Retinal vein occlusion 
Confidential
Page 18 of 517

SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SD-OCT 
spectral domain – optical coherence tomography 
SID 
Subject Identification 
SPC 
Summary of Product Characteristics 
TEAE 
Treatment emergent adverse event 
US 
United States 
VEGF 
Vascular Endothelial Growth Factor 
WoCBP 
Women of Child-Bearing Potential 
Confidential
Page 19 of 517

1 STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to the Study Conduct Section (6) for detailed 
information on each procedure and assessment required for compliance with the protocol. 
Figure 1: Study Diagram 
 
Confidential
Page 20 of 517

The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to the Study Conduct Section (Section 6) for 
detailed information on each procedure and assessment required for compliance with the protocol. 
Table 1: Study Schedule 
Assessme
nt 
Period 
Scree
ning 
Treatment period 
Visit 
Scree
ning 
Visit  
V1/ 
BL 
V2q 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
V7A
p 
V8 
V9 
 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
 
Day or 
week: 
D -28 
to  
D -1 
D1 
D3 
(±0 
d) 
W1 
(±2d) 
W4 
(±3d) 
W8 
(±3d) 
W12  
(±7d) 
W16 
(±7 d) 
W16 
+2d 
(±0 
d) 
W20 
(±7d) 
W24 
(±7d) 
W28 
(±7d) 
W32 
(±7d) 
W36 
(±7d) 
W40 
(±7d) 
W44 
(±7d) 
W48 
(±7d) 
W52 
(±7d) 
EOS/ 
ET 
Informed Consenta 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Surgical 
and Ophthalmic 
historyb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/weight 
x 
xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xc 
Pregnancy testd 
x 
x 
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical Safety 
Laboratorye 
x 
x 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
PT, aPTT and INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT, aPTT and INR 
for patients in Czech 
Republic only 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
Targeted Physical 
Examinationf 
x 
x 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Vital Signsg 
x 
x 
 
x 
x 
x 
x 
x 
 
xh 
x 
xh 
x 
xh 
x 
xh 
x 
x 
12- Lead  
Electrocardiogrami 
x 
x 
 
x 
 
 
 
 
 
 
x  
 
 
 
 
 
 
x 
Complete 
Ophthalmologic 
Examinationj 
x 
x 
xr 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Best Corrected 
x 
x 
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Confidential
Page 21 of 517

Assessme
nt 
Period 
Scree
ning 
Treatment period 
Visit 
Scree
ning 
Visit  
V1/ 
BL 
V2q 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
V7A
p 
V8 
V9 
 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
 
Day or 
week: 
D -28 
to  
D -1 
D1 
D3 
(±0 
d) 
W1 
(±2d) 
W4 
(±3d) 
W8 
(±3d) 
W12  
(±7d) 
W16 
(±7 d) 
W16 
+2d 
(±0 
d) 
W20 
(±7d) 
W24 
(±7d) 
W28 
(±7d) 
W32 
(±7d) 
W36 
(±7d) 
W40 
(±7d) 
W44 
(±7d) 
W48 
(±7d) 
W52 
(±7d) 
EOS/ 
ET 
Visual Acuity 
(Bilateral) 
Spectral Domain – 
Optical Coherence 
Tomography / 
Central Retinal 
Thickness 
(Bilateral) 
x 
x 
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fluorescein 
Angiography/ 
Fundus Photography 
(Bilateral) k 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Randomizationl 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
administration 
 
x 
 
 
x 
x 
x 
x 
 
xh 
x 
xh 
x 
xh 
x 
xh 
x 
 
Pharmacokinetic 
blood samplingm 
 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
Immunogenicity 
blood samplingn 
 
x 
 
x 
x 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
Drug Tolerance 
blood samplingn 
 
x 
 
x 
x 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
Adverse eventso 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record Concomitant 
medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Diary 
Issue/ReviewS 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abbreviations: aPTT = activated partial thromboplastin time; BL = baseline visit; EOS = end of study; ET = Early Termination; INR = International Normalized Ratio  
PT = Prothrombin Time  
Note: An unscheduled visit may be necessary and can occur at any time if the Investigator believes it is essential for any reason 
Confidential
Page 22 of 517

a. 
Written informed consent will be obtained prior to the initiation of any study related procedures 
b. Medical, surgical, ophthalmic and smoking history, and current medical conditions and medications 
c. 
Weight only 
d. Female subjects of child bearing potential will have a serum pregnancy test at screening and at the EOS visit (Study Week 52) and urine pregnancy test at other identified 
visits 
e. 
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be obtained before study drug administration 
f. 
A targeted physical examination will be performed. If indicated, based on report of adverse events or result of safety laboratory test, directed physical exam will be 
performed at additional visits 
g. Vital signs include blood pressure (BP), pulse rate and temperature. BP will be measured after the subject is sitting for 5 mins  
h. Additional doses may be administered at Week 20, Week 28, Week 36 and Week 44 based on the visual acuity, and/or SD-OCT at that visit and in accordance with 
protocol specified criteria for administering additional 4-weekly doses. If an additional dose is administered, collect vital signs before the study drug administration 
i. 
12-lead Electrocardiogram will be conducted before study drug administration 
j. 
Ophthalmologic examination includes slit lamp examination, indirect ophthalmoscopy and intraocular pressure measurement in study eye. Slit lamp examination, 
indirect ophthalmoscopy and intraocular pressure (IOP) measurement will be done before study drug administration and measurement of IOP and finger counting will be 
done approximately 30 minutes after study drug administration 
k. Fluorescein Angiography/Fundus Photography will be done after BCVA testing and other investigations including blood and urine samples are collected 
l. 
On Day 1 prior to study drug administration, subjects will be randomized 1:1 to receive either MYL-1701P or Eylea  
m. Pharmacokinetic blood samples will be taken only in patients that are part of the PK subpopulation, before study drug administration. The blood sampling collected for 
drug tolerance on visits (V1, V3, V4, V5, V7, V9, V11, V13, V16) will be used for PK evaluation 
n. Immunogenicity (ADA/NAb) and drug tolerance blood samples will be taken before study drug administration whenever applicable. Additional immunogenicity samples 
will be collected if subject has signs of intraocular inflammation suggesting immune reaction  
o. Ocular Adverse Events (AEs) and non-ocular AEs will be collected and analyzed separately. Ocular AEs for the study eye and the fellow eye will be collected and 
analyzed separately 
p. Week 16+2 days visit will be conducted only for subjects participating in subset PK evaluation 
q. Visit 2 (Day 3) will be performed at clinic only for the subjects in sentinel cohort and subjects in PK subset. For all other subjects, it will be a telephonic visit 
r. 
Ophthalmological examination on Visit 2 (Day 3) will be conducted only for subjects in the sentinel cohort 
s. 
Study Diary will be issued during V1/BL, reviewed during subsequent visits, and returned during the V16/EOS or ET visit. Study diary will be used by subjects to record 
the AEs and concomitant medications in between the study visits 
Confidential
Page 23 of 517

2 INTRODUCTION 
2.1 Indication 
Mylan Inc., in collaboration with Momenta Pharmaceuticals, Inc. is developing a proposed 
biosimilar version of Eylea® (aflibercept). Eylea was first approved in 2011 by US FDA for 
treatment of wet Age-Related Macular Degeneration. 
Eylea (aflibercept) is a vascular endothelial growth factor (VEGF) inhibitor indicated for the 
following treatments in the US and EU: 
• Neovascular (Wet) Age-Related Macular Degeneration (AMD) 
• Macular Edema Following Retinal Vein Occlusion (RVO) 
• Diabetic Macular Edema (DME) 
Additionally, it is indicated for Diabetic Retinopathy in Patients with DME in the US and 
visual impairment due to myopic choroidal neovascularization in the EU. 
This study is being conducted by Mylan to demonstrate the clinical similarity of MYL-1701P 
(a proposed biosimilar to Eylea, also referred to as M710) and Eylea with regard to efficacy, 
safety, pharmacokinetics and immunogenicity in the treatment of patients with DME. 
2.2 Background and Rationale 
Diabetic retinopathy is a common cause of blindness worldwide. The International Diabetes 
Federation estimates that 285 million people worldwide have diabetes mellitus and that 7% of 
these individuals are affected by diabetic macular edema (Whiting DR, 2011; Ding J et al., 
2012). 
Anti-VEGF drugs are effective at improving vision in people with DME. Eylea (aflibercept) 
confers some advantage over ranibizumab and bevacizumab in people with DME, at one year 
in both visual and anatomic terms. (Virgili G et al., 2017). 
MYL-1701P is being developed as a proposed biosimilar to Eylea (aflibercept). Eylea is a 
recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 
extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic 
solution for intravitreal administration. Eylea is being marketed by Regeneron 
Pharmaceuticals, Inc. in the US and Bayer AG in EU. 
Complete information of the investigational medicinal product for MYL-1701P-3001 is 
available in the Single Reference Safety Document, which for this study is the MYL-1701P 
Investigator’s Brochure. 
Throughout this study protocol, “Eylea” refers to US-licensed Eylea. 
2.2.1 Rationale for Study 
MYL-1701P is currently being developed by the sponsor (Mylan Inc.) in collaboration with 
Momenta Pharmaceuticals, that is being formulated as a proposed biosimilar to Eylea in 
accordance with European Union (EU) and US Biosimilar guidelines. (EMA 2014, 
FDA 2015) 
This is a multi-center, randomized, double-masked, active-controlled, comparative clinical 
study to demonstrate that no clinically meaningful differences exist between MYL-1701P and 
US-licensed Eylea in subjects with DME treated up to 52 weeks. 
It is part of the overall registration package to support the regulatory approval of MYL-1701P 
as a proposed biosimilar to Eylea.  
Confidential
Page 24 of 517

2.2.1.1 Rationale for Study Population- Diabetic Macular Edema 
The active pharmacologic agent, in Eylea (aflibercept), is understood to act as a soluble 
decoy receptor that binds to VEGF-A and PlGF, and thereby inhibits the binding and 
activation of their cognate receptors VEGFR-1 and VEGFR-2, which are expressed on the 
surface of endothelial cells. Activation through VEGFR-1 and VEGFR-2 is associated with 
neovascularization and vascular permeability, while inhibition of activation by Eylea 
(aflibercept) has been demonstrated to reduce both processes, with clinical benefit in the 
indicated disorders. (Eylea US Package Insert, 2017).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
2.2.1.2 Rationale for Subject Selection and Study Endpoints 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
It is recognized that baseline visual acuity can be a factor in treatment response. In 
Dugel PU et al., 2016, treatment response was analyzed by categories of baseline BCVA for 
several anti-VEGF treatments, but with greatest focus on trials of Lucentis. It was 
demonstrated that change in BCVA increased as baseline BCVA decreased. Therefore, to 
reduce variability, randomization will be stratified based on Baseline BCVA, i.e., ETDRS 
letter scores 73-55 vs. 54-38 and geographical region (US, EU, Japan and rest of the world). 
(Dugel PU et al., 2016) In addition, baseline BCVA is included as a covariate in the primary 
analysis. 
Confidential
Page 25 of 517

Change from baseline in BCVA is a clinically relevant endpoint and being a continuous 
variable is adequately sensitive to detect any clinically meaningful differences between study 
treatments. Hence mean change in BCVA is considered as the primary endpoint for the 
current study. Central retinal thickness is being evaluated as a key secondary endpoint. CRT 
assesses the pharmacodynamic aspects of aflibercept and is supportive in detecting 
differences between study treatments (MYL-1701P and Eylea). 
2.3 Study Design 
This is a multi-center, randomized, double-masked, active-controlled, comparative clinical 
study between MYL-1701P and US-licensed Eylea in subjects with DME treated up to 52 
weeks. 
A total of 324 eligible adult subjects with type 1 or 2 diabetes mellitus with central DME 
involvement and BCVA between 73 and 38 letters based on ETDRS letters (20/40 – 20/200 
Snellen equivalent) in the study eye with CRT > 300 µm, as determined by SD-OCT, in the 
study eye will be randomized 1:1 to intravitreal treatment with MYL-1701P or Eylea. 
 
 
 
 
 
 
At study week 8, the primary endpoint will be assessed, and subjects will continue to receive 
the assigned treatment until Week 48. An end of study visit will be conducted at Week 52.  
Subjects will receive intravitreal injections of either MYL-1701P or Eylea throughout the 
52-week treatment period, with planned doses at Study Day 1, Day 29 (week 4), Day 57 
(week 8), Day 85 (week 12), Day 113 (week 16), Day 169 (week 24), Day 225 (week 32), 
Day 281 (week 40) and Day 337 (week 48).  
In addition to the nine planned doses, study drug may also be administered at Week 20, 
Week 28, Week 36 and Week 44 based on the current visual acuity, and or SD-OCT at that 
visit and in accordance with the “criteria for administering additional 4-weekly doses” 
outlined in Section 5.1.2.  
Both US Package Insert (USPI) and EU Summary of Product Characteristics (SPC) for Eylea 
recommends intravitreal injection every 4 weeks (monthly) for the first 5 injections followed 
by intravitreal injection once every 8 weeks (2 months), USPI also allows additional every 4-
week (monthly) dosing in some subjects based on the need. However, SPC does not make 
any such recommendations for 4 weekly dosing after 5 injections.  
The current study allows for additional optional doses after 5 initial monthly injections if 
deemed necessary as per the prespecified criteria. Additional efficacy was not demonstrated 
in most subjects when Eylea was dosed every 4 weeks compared to every 8 weeks. Hence, 
most of the subjects may not require additional 4-weekly doses. Whenever the Investigator 
decides to administer additional doses, they must satisfy the criteria outlined in Section 5.1.2 
and should also weigh the procedural risks related to intravitreal injection versus potential 
benefit. 
All subjects will return to clinic every 4 weeks for assessment of visual acuity (BCVA based 
on ETDRS letters) and central retinal thickness (CRT by SD-OCT) to assess efficacy and to 
guide treatment. There will be additional visits during the study as specified in the study visit 
schedule for safety and pharmacokinetic evaluation.  
Randomization will be stratified by BCVA at baseline (ETDRS Letter Scores 73-55 vs 
54-38) and geographical region (US, EU, Japan and Rest of the World).  
Confidential
Page 26 of 517

Immunogenicity will be evaluated for all the subjects participating in the study, through 
assessment of blood samples collected prior to study drug administration for anti-drug 
antibodies and neutralizing antibodies. Along with immunogenicity, free drug concentration 
in the blood samples from all subjects will be determined to evaluate drug tolerance status. 
2.3.1 Pharmacokinetic Subpopulation 
At least 32 subjects in each study arm will be included in the pharmacokinetic (PK) subset 
and PK sampling will be done in these subjects as per the Study Schedule (Table 1). These 
subjects will be enrolled from identified participating Investigator sites after voluntary 
consent for the same. These subjects will be required to visit the study site for PK sampling 
for 2 additional visits V2 and V7A, scheduled 48 hours after the first dose and fifth dose of 
study drug administration respectively. 
 
 
 
 
 
 
 
 
 
2.3.3 Reporting Strategy 
 
 
 Complete 
efficacy, safety, pharmacokinetics and immunogenicity data through Week 52 will be 
included in the 52-week CSR.  
 
  
 
 
 
  
 
2.4 Potential Risks 
There are no clinical data available on MYL-1701P in humans or animals. Although 
MYL-1701P has not yet been used in a clinical setting, comparative physiochemical 
characterization and biological characterization conducted to date showed a high degree of 
similarity between MYL-1701P and Eylea. 
The adverse reactions available for the reference product, Eylea, could be reasonably 
assumed to be associated with MYL-1701P, and therefore considered expected for the 
purposes of expedited reporting to regulatory authorities and investigators. The excipients in 
the formulation of MYL-1701P are different from that of the Eylea formulation. Investigator 
should consider this difference between MYL-1701P and Eylea, while evaluating history of 
hypersensitivity to any of the excipients.  
Confidential
Page 27 of 517

However, because MYL-1701P has not yet been evaluated in clinical studies, investigators 
should carefully monitor for all adverse events, including those not described as associated 
with Eylea and should promptly document and report the adverse events as per the protocol. 
2.4.1 Safety Profile of Eylea 
A complete overview of the undesirable effects of Eylea can be found in the Eylea SPC and 
Eylea USPI. (Eylea SPC, 2017 and Eylea US Package Insert, 2017). 
The adverse events of particular concern include but are not limited to: 
• Endophthalmitis and retinal detachment following intravitreal injections: In such an 
event subject, should be instructed to report any symptoms suggestive of 
endophthalmitis or retinal detachment without delay and should be managed 
appropriately.  
• Increases in intraocular pressure after intravitreal injection. 
• Potential risk of arterial thromboembolic events following intravitreal use of VEGF 
inhibitors; these events will be classified according to Hicks et al, 2018 by an 
Independent Cardiovascular Adjudication Committee 
The most common adverse reactions (≥5%) reported in patients receiving Eylea were 
conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, 
and vitreous detachment. 
As this is a therapeutic protein, there is a potential for immunogenicity with 
Eylea/MYL-1701P. Subjects should be instructed to report any signs or symptoms of 
intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign 
attributable to hypersensitivity. 
For any potential allergic reaction after administration of study drug, diagnosis and 
assessment of anaphylaxis will be done using National Institute of Allergy and Infectious 
Disease and the Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria of 
anaphylaxis; the management of anaphylaxis should follow the standard institutional 
practices (Appendix 11.1). 
2.4.2 Intravitreal injections 
The drugs used to anesthetize the eye before injections can cause an allergic reaction, 
seizures and irregular cardiac rhythm.  
Subconjunctival hemorrhage or floaters may occur because of intra-vitreal injection. Mild 
discomfort, ocular hyperemia, increased lacrimation, discharge or itching may occur which 
may last for few days.  
There may be an elevation of intraocular pressure immediately following the injection. It 
usually returns to normal spontaneously but may need treatment with topical drugs or a 
paracentesis to lower the pressure.  
As a result of the injection, endophthalmitis can develop and it is treated by intravitreal 
injection of antibiotics, but there is a risk of permanent loss of vision including blindness. 
Retinal detachment can also occur as a result of the injection. If this occurs, surgical 
intervention may be required. The injection could also cause a vitreous hemorrhage. This 
usually resolves spontaneously, although surgical intervention may be required. 
Confidential
Page 28 of 517

2.4.3 Eye examination and Investigations 
There is a rare risk of an allergic response to the topical medications used to anesthetize the 
eye or dilate the pupil. There may be other adverse events related to the topical medications 
used, for which respective prescribing information should be referred. 
There are no known risks associated with SD-OCT or fundus photographs. The bright flashes 
used to take the photographs may be annoying but are not painful and cause no damage. 
 
Confidential
Page 29 of 517

3 OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
3.1.1 Primary objective 
The primary objective is to demonstrate the clinical equivalence of MYL-1701P and Eylea 
over 8 weeks of treatment at doses and regimen recommended by the Prescribing Information 
for Eylea, as assessed by change from baseline to week 8 in BCVA. 
3.1.2 Secondary objectives 
The key secondary objective is: 
• To compare the efficacy of MYL-1701P and Eylea as measured by change in CRT 
over time  
The other secondary objectives are: 
• To compare the efficacy of MYL-1701P and Eylea as measured by change in BCVA 
over time  
• To compare safety, tolerability, pharmacokinetics, and immunogenicity over time of 
MYL-1701P and Eylea 
• To compare the number of administrations of study drug required over the treatment 
period 
• To compare impact of immunogenicity on efficacy and safety 
3.2 Endpoints 
3.2.1 Primary Endpoints 
The primary efficacy endpoint will be the mean change from baseline in BCVA as assessed 
by ETDRS letters at week 8. 
3.2.2 Secondary Endpoints 
3.2.2.1 Efficacy 
The key secondary efficacy endpoint is 
• The mean change from baseline in CRT as determined by spectral-domain-optical 
coherence tomography (SD-OCT) over time 
The other secondary efficacy endpoints will include: 
• The mean change in BCVA over time  
• Proportion of subjects who gained ≥15 letters from Baseline in BCVA, assessed in 
change from baseline in ETDRS letters over time 
• Number of administrations of study drug required  
3.2.2.2 Safety 
Safety and tolerability will be assessed over time, based on the following evaluations: 
• Ocular (study eye and fellow eye) and non-ocular adverse events (AE) 
• Vital signs 
• Physical examinations performed 
• Complete ophthalmological examination (OE) 
• Safety labs (serum chemistry, hematology, and urinalysis) 
• Twelve-lead electrocardiograms (ECGs) 
Confidential
Page 30 of 517

3.2.2.3 Immunogenicity 
Anti-Drug Antibodies to aflibercept: occurrence, titer, and neutralizing capacity 
3.2.2.4 Pharmacokinetics 
Concentration of aflibercept (free drug) 
 
Confidential
Page 31 of 517

4 STUDY POPULATION 
4.1 Study Population 
A total of 324 subjects are planned to be randomized into the study to ensure to have 290 
subjects complete the study. One extra subject will be randomized for each subject who 
meets any of the pre-specified criteria related to missed/delayed dosing or study assessments 
because of the COVID-19 pandemic. The maximum number of these extra subjects will be 
70. 
Study duration from screening to end of study can be up to 13 months/56 weeks 
approximately. 
4.2 Sample Size Considerations 
 
 
 A total of 324 subjects will be 
randomized to each arm after allowing for approximately 10% drop-outs. 
 
 
 
4.3 Inclusion and Exclusion Criteria 
4.3.1 Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible to participate in the 
study: 
1. Male or female subjects age ≥ 18 years. For Japan, in case of a subject under 20 years 
old, his/her legally acceptable representative should provide the informed consent for 
the study participation. 
2. Subjects have type 1 or type 2 diabetes mellitus who present with central DME 
involvement (defined as retinal thickening with a measurement of 300µm or more 
involving the 1 mm CRT by SD-OCT) in the study eye. 
3. The cause of decreased vision in the study eye has been attributed primarily to DME 
by the Investigator. 
4. Subjects must have BCVA at 4 m from 73 to 38 letters (ETDRS chart) equivalent to 
Snellen visual acuity of 20/40 to 20/200 in the study eye. 
5. Subject is able to understand and voluntarily provide written informed consent to 
participate in the study. 
6. If female of child bearing potential, the subject must have a negative serum pregnancy 
test at the Screening visit and a negative urine pregnancy test at baseline visit, and 
should not be nursing or planning a pregnancy. 
7. If female, subject must be: 
a. Surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation; or 
Confidential
Page 32 of 517

b. Of childbearing potential and practicing an acceptable form of birth control 
(defined as the use of an intrauterine device; a barrier method, like condom, 
with spermicide; any form of hormonal contraceptives; or abstinence from 
sexual intercourse) starting 60 days prior to dosing and continuing at least 90 
days following the last treatment.  
c. Of non-childbearing potential (i.e., postmenopausal for at least 1 year). 
For Japan: If female, subject must be: 
• Of non-childbearing potential (i.e., surgically sterilized via hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation, or postmenopausal* for at 
least 1 year); 
* definition: she is not menstruating for at least 12 months without any other 
medical reason. 
• Of childbearing potential and practicing an acceptable form of birth control 
(defined as the use of an intrauterine device; a barrier method, like condom, 
with spermicide; any form of hormonal contraceptives; or abstinence from 
sexual intercourse) starting 60 days prior to dosing and continuing at least 90 
days following the last treatment 
For Czech Republic: If female, must be permanently sterile or subject must be using a 
birth control method, which is considered as highly effective (described in detail in 
Section 4.4.2), starting 60 days prior to dosing and continuing at least 90 days 
following the last treatment 
8. If male, subject must be surgically or biologically sterile. If not sterile, the subject 
must agree to use an acceptable form of birth control with sexual partner (as described 
in inclusion criteria #7b) or abstain from sexual relations during the study period and 
up to 90 days following the last treatment dose. 
For Czech Republic: If male, subjects should use highly effective method of 
contraception starting 60 days prior to dosing and continuing at least 90 days 
following the last treatment (described in detail in Section 4.4.3). 
9. Subject is willing to comply with the study duration, study visits and study related 
procedures. 
4.3.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subjects with known hypersensitivity to aflibercept or any of the excipients in 
MYL-1701P and Eylea 
2. Known hypersensitivity to fluorescein 
3. Ocular media of insufficient quality to obtain fundus and OCT images 
4. Subjects will be excluded if any of the following conditions are met in the study eye: 
a. Subjects with a history of vitreoretinal surgery in study eye and/or including 
scleral buckling 
b. Subjects who have had panretinal or macular laser photocoagulation within 3 
months of randomization 
Confidential
Page 33 of 517

c. Subjects with history of use of intraocular corticosteroids anytime in the past 
or periocular (subconjunctival, intra-scleral, sub-tenon or retrobulbar) 
corticosteroids within 4 months of randomization 
d. Subjects who have reduced vision due to causes other than DME, with the 
exception of requirement for spherical correction, or mild cataract assessed by 
the Investigator as not interfering with assessment of BCVA or CRT 
e. Subjects with active proliferative diabetic retinopathy 
f. Subjects with active ocular inflammation 
g. Subjects who have had cataract or other intraocular surgery within 3 months of 
randomization or expected to undergo cataract surgery or capsulotomy during 
the study duration 
h. Subjects who have had laser capsulotomy within 3 months of randomization 
i. Subjects with aphakia, whether congenital or surgical 
j. Subjects with vitreous hemorrhage 
k. Subjects with visually significant vitreomacular traction or epiretinal 
membrane evident biomicroscopically or on OCT that is thought to affect 
central vision 
l. Subjects with myopia of spherical equivalent of ≥ - 8 diopters, prior to any 
possible refractive or cataract surgery 
m. Subjects with any other disease that might compromise visual acuity or require 
medical or surgical intervention during the study period, or could confound 
interpretation of the results (including retinal vascular occlusion, retinal 
detachment, macular hole or choroidal neovascularization of any cause) 
n. Structural damage to the center of the macula that is likely to preclude 
improvement in BCVA following the resolution of macular edema including 
atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, 
significant macular ischemia or organized hard exudates based on the 
Investigator’s discretion with help of FA/FP and OCT. 
o. Subjects with uncontrolled glaucoma (defined as intraocular pressure ≥ 25 
mmHg despite treatment with antiglaucoma medication); subjects with 
controlled glaucoma may participate in the study. [For India - Subjects with a 
clinical diagnosis of glaucoma (controlled or uncontrolled)]. 
p. Surgery for glaucoma in the past or likely to be needed in the future 
q. Intraocular pressure ≥25 mm of Hg in the study eye 
r. Prior treatment with verteporfin (photodynamic therapy) 
5. Subjects will be excluded if any of the following conditions are met in either eye: 
a. Subjects with active iris neovascularization 
b. Subjects with preretinal fibrosis involving the macula 
c. Subjects with history of idiopathic or autoimmune uveitis 
d. Subjects with active or suspected ocular or peri-ocular infection including but 
not limited to infectious blepharitis, keratitis, scleritis, or conjunctivitis 
Confidential
Page 34 of 517

6. Subjects who received previous therapy with antiangiogenic drugs for either eye 
(pegaptanib, bevacizumab, ranibizumab, aflibercept). 
7. Subjects who have received previous systemic antiangiogenic drugs (bevacizumab, 
aflibercept). 
8. Subjects with current or planned use of systemic medications known to be toxic to the 
lens, retina or optic nerve, including deferoxamine, chloroquine/hydroxychloroquine, 
tamoxifen, phenothiazines and ethambutol. 
9. Subjects who plan to participate in another clinical study while enrolled in this study 
and/or who have received an investigational drug and/or device within 30 days or 5 
half-lives, whichever is longer, prior to screening. 
10. Subject receiving treatment for a serious systemic infection. 
11. Subjects with uncontrolled diabetes mellitus as defined by HbA1c ≥10% at screening 
12. Subjects with uncontrolled hypertension defined as systolic blood pressure > 160 mm 
Hg or diastolic blood pressure > 95 mm of Hg.  
13. Subjects with a history of cerebrovascular accident or myocardial infarction within 6 
months of randomization. 
14. Subjects with renal failure requiring dialysis or renal transplant. 
15. Subjects who have only one functional eye, even if the eye met all other study 
requirements, or who have an ocular condition on the fellow eye with a poorer 
prognosis than the study eye. 
16. Presence or history of malignant neoplasm (including lymphoproliferative disease), 
except for adequately treated basal cell carcinoma and cervical carcinoma in situ; or 
any malignancy with complete remission of more than 5 years. 
17. Subjects with a history or presence of clinically significant cardiovascular, 
pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, 
dermatologic, neurologic, oncologic, psychiatric disease, or any other condition, that 
in the opinion of the Investigator would jeopardize the safety of the subject or the 
validity of the study results. 
4.3.3 Criteria for study drug termination, withdrawal from the study and study 
termination 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center.  
Every effort should be made to retain subjects in the study. When available, a reason for not 
completing the study will be recorded in the electronic case report form (eCRF). 
If, a subject discontinues from the study prematurely, due to any reason as provided in the below 
withdrawal criteria, the site should request the subjects’ consent for being followed-up during 
further study visits or at least until the Week 8 to perform safety and efficacy assessments as 
per the Study Schedule (Table 1).  
A subject may be required to terminate study drug for reasons including the following: 
• The subject withdraws consent. 
• 
For female subjects, diagnosis of pregnancy or stated intention to become pregnant. All 
efforts should be made by the site to obtain consent from the pregnant women, so that 
they are followed until delivery or termination. 
Confidential
Page 35 of 517

• At the investigator’s discretion (it is recommended that the investigator discusses with 
medical monitor prior to decision), if it is in the subject’s best interest due to 
occurrence of an AE and/or other findings considered to present a safety concern to 
continued dosing with study drug, which include but not limited to: 
o Development of hypersensitivity reaction suspected to be attributable to study 
drug which may contraindicate the continued dosing with the study drug  
o Development of ocular or periocular infection, active intraocular inflammation 
which may contraindicate the continued dosing with the study drug 
• Despite education/reinforcement, the subject shows persistent inadequate compliance 
with required study visits/procedures, potentially compromising safety monitoring 
while on study drug based on investigator’s discretion. 
• The subject takes prohibited treatment presenting a safety concern to continued 
dosing with study drug 
• At the investigator’s discretion (it is recommended that the investigator discusses with 
medical monitor prior to decision), in certain situations such as disease flare, 
progression, or nonresponse that requires treatment with a prohibited medication or 
procedure, which in the opinion of the investigator warrants treatment withdrawal.  
• If the mask is broken for a subject by the Investigator  
Subjects who prematurely terminate study will have an Early Termination (ET) visit 
scheduled as soon as possible.  
The Principal Investigator and/or Mylan reserves the right to terminate the study for any 
reason. 
The study will be terminated early if there are significant safety concerns. 
4.4 Contraception 
4.4.1 Females - Non-Childbearing Potential 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
1. Postmenopausal females, defined as females, 45 years of age or more, and who have been 
amenorrheic for at least 1 year. 
2. Females who have a documented hysterectomy and/or bilateral oophorectomy. 
All other females will be considered to be of childbearing potential. 
For patients in Czech Republic, following are applicable: 
Females - Non-Childbearing Potential (Permanently sterile) 
Female subjects of non-childbearing potential (permanently sterile) must meet at least one of 
the following criteria: 
1. Postmenopausal females, defined as females, 45 years of age or more, and who have been 
amenorrheic for at least 1 year, without an alternative medical cause. 
2. Females who have a documented hysterectomy, bilateral salpingectomy and/or bilateral 
oophorectomy. 
All other females will be considered to be of childbearing potential. 
4.4.2 Females - Childbearing Potential 
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e., a method with a failure rate <1% when used consistently and correctly) 
Confidential
Page 36 of 517

starting 60 days prior to dosing and continuing at least 90 days following the last treatment, 
such methods include at least one of the following: 
• Abstinence (periodic abstinence is not acceptable) 
• Tubal ligation* 
• Intrauterine device of intrauterine system* 
• Barrier method, like condom*, with spermicide* 
• Male partner who has had a vasectomy for at least 6 months. Male partners with 
vasectomies of <6 months are NOT considered protected 
• Hormonal contraceptives (oral*, injected, transdermal or implanted) with the 
exception of low dose gestagens, i.e. only containing lynestrenol or norethisterone, 
since they do not inhibit ovulation and are therefore not considered as highly-
effective. The subject must remain on the hormonal contraceptive throughout the 
study and must have been using hormonal contraceptives for an adequate period prior 
to the study to ensure effectiveness (e.g., 3 months) 
*: For patients in Japan, it must be approved or certified in Japan 
For patients in Czech Republic, following are applicable: 
Females - Childbearing Potential 
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e., a method with a failure rate <1% per year when used consistently and 
correctly) starting 30 days prior to dosing and continuing at least 90 days following the last 
treatment, such methods include at least one of the following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
o Oral 
o Intravaginal  
o Transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral  
o Injectable  
o Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)  
• Bilateral tubal occlusion  
• Vasectomised partner (Vasectomised partner is a highly effective birth control method 
provided that partner is the sole sexual partner of the WOCBP trial participant and 
that the vasectomised partner has received medical assessment of the surgical success) 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments) 
4.4.3 Male subjects (only for patients in Czech Republic) 
Male subjects should use highly effective method of contraception starting 30 days prior to 
dosing and continuing at least 90 days following the last treatment, such methods include at 
least one of the following: 
• Vasectomy with confirmation of success from the doctor 
• Consistent use of condom 
• Absolute sexual abstinence (refrain from vaginal intercourse) 
Confidential
Page 37 of 517

4.5 Pregnancy Testing 
Serum or urinary pregnancy testing will be performed on all females of childbearing potential 
as described in the schedule of activities (results will be reviewed and must be negative prior 
to dosing). In the event of a positive test, the subject will be withdrawn from the study (or 
will not enter the study if during screening). 
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the sponsor as per Section 9.4.1. 
Confidential
Page 38 of 517

5 STUDY DRUG 
5.1 Investigational Drug 
Test Product, Dose, and Mode of Administration:  
MYL-1701P (a proposed biosimilar to Eylea) injection for intravitreal injection is a sterile, 
clear, and colorless to pale yellow solution. It is supplied as a preservative-free, sterile, 
aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 µL) of proposed 
aflibercept (40 mg/mL) 
 
 
Reference Therapy, Dose, and Mode of Administration:  
Eylea is a sterile, clear, and colorless to pale yellow solution. It is supplied as a 
preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 
mL (50 µL) of Eylea (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 
0.03% polysorbate 20, and 5% sucrose). Eylea will be sourced from the United States. 
5.1.1 Administration of Study Drugs 
All subjects are planned to receive study drug as an intravitreal injection at a dose of 2 mg 
every 4 weeks for a total of 5 injections, and then every 8 weeks through the remainder of the 
52-week treatment period, with the last dose at 48 weeks. 
Subjects will receive intravitreal injections of MYL-1701P or Eylea throughout the 52-week 
treatment period, with planned doses at Study Day 1, Day 29 (week 4), Day 57 (week 8), 
Day 85 (week 12), Day 113 (week 16), Day 169 (week 24), Day 225 (week 32), Day 281 
(week 40) and Day 337 (week 48).  
In addition to the nine planned doses, study drug may also be administered at Week 20, 
Week 28, Week 36 and Week 44 based on the visual acuity, and/or SD-OCT at that visit and 
in accordance with the “criteria for administering additional 4-weekly doses” outlined in 
Section 5.1.2.  
5.1.2 Criteria for administering additional 4-weekly doses 
 
 
 
  
 
 
 
  
 
 
 
 
Additional efficacy has not been demonstrated in most subjects when Eylea was dosed every 
4 weeks compared to every 8 weeks. Hence, most of the subjects may not require additional 
4-weekly doses. 
5.1.3 Delayed and Missed Visits and/or Dose 
Every attempt should be done to complete the visits and/or dosing with in the given window 
period for each scheduled visit. The out of window drug administration should be recorded as 
a protocol deviation. 
If dose is given late for unavoidable reasons, the next scheduled dose should occur no sooner 
than three weeks after the previous dose. The next dose should be scheduled such that it is as 
Confidential
Page 39 of 517

close as possible to the original scheduled date of visit and at least 3 weeks apart from the 
previous dose. Investigators should ensure that the subjects’ general clinical and the ocular 
conditions are suitable for dosing prior to every dosing. 
If the visit is delayed until the start of the window period of the next dose, the visit will be 
considered as a missed visit. 
The reasons for the delayed or missed visits and/or doses must be documented in the patient’s 
study records and appropriate section of the eCRF and all efforts should be taken to 
administer the subsequent scheduled doses on time. 
5.1.4 Administration Procedure 
MYL-1701P must only be administered by a qualified person and the dosing regimen is 
expected to be the same as the current labeling for Eylea. Intravitreal injections should not be 
performed if the pre-dose intra-ocular pressure is more than 30 mm Hg. (Eylea EU SPC, 
2017) 
The intravitreal injection procedure should be carried out under controlled aseptic conditions, 
which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a 
sterile eyelid speculum (or equivalent). 
Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the 
injection. The choice of the anesthetic agent and the microbicide can follow institutional 
practices. The details of the pre-medication administered should be documented. 
Immediately following the intravitreal injection, subjects should be monitored for elevation in 
intraocular pressure. If required, a sterile paracentesis needle should be available. 
Additionally, vision will be assessed post-injection by hand movements or counting fingers. 
Following intravitreal injection, subjects should be instructed to report any symptoms 
suggestive of intraocular inflammation, endophthalmitis and/or retinal detachment (e.g., eye 
pain, redness of the eye, photophobia, blurring of vision) without delay. 
If the subject reports any of these symptoms, Investigator will perform OE and appropriate 
investigations to confirm the diagnosis. Additional immunogenicity samples will be collected 
if subject has signs of intraocular inflammation, suggesting immune reaction. 
Each vial should only be used for the treatment of a single eye. After injection, any unused 
product must be discarded. 
In the event of any significant dosing errors, the CRO Medical Monitor, or designee should 
be contacted immediately. 
5.2 Drug Inventory 
Mylan will supply MYL-1701P and US-reference Eylea to the study sites packaged and 
labeled per all local legal requirements. 
Clinical Supplies will provide prepackaged supplies for each subject. A kit will be assigned at 
randomization using the IXRS. 
A label will be attached to the outside of each kit. The text will be compliant with local 
regulatory requirements and may include some of the following information: 
• Protocol number 
• Subject number/study center number 
• Contents and quantity 
• Lot number 
Confidential
Page 40 of 517

• Randomization code/kit number 
• Investigator name 
• Storage instructions 
• Caution statement (for clinical study use only) 
• Expiry date 
• Sponsor’s name and address 
5.3 Study Medication Complaints 
In the event of a complaint/concern during study participation, regarding the supplied study 
medication, the site should contact the sponsor. Additional information and potentially the 
return of study medication may be requested by Mylan to investigate the complaint. The 
details of the complaint handling will be provided in an appropriate study manual. 
5.4 Storage, Disposition of Unused Study Drug and Drug Accountability 
The Investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the investigator site. 
Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage. 
Temperature of storage facilities should be monitored and recorded daily using validated 
devices that record maximum and minimum temperatures. Should the storage facility 
experience any excursion of temperature outside of the labelled storage condition this must 
be reported immediately to Mylan or designee. At sites where daily monitoring and recording 
is not possible at weekends, then on the next working day after the weekend the temperature 
record (e.g., max/min thermometers) should be checked immediately for any temperature 
excursions. Devices used for temperature monitoring should be regularly calibrated. Affected 
material must be placed into quarantine until the impact of the excursion has been assessed 
and confirmed by Mylan.  
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. If Mylan or CRO supplies drug accountability forms, these 
must be used. Alternatively, Mylan may approve use of standard institution forms. In either 
case, the forms must identify the study drug, including batch or code numbers, and account 
for its disposition on a subject-by-subject basis, including specific dates and quantities. The 
forms must be signed by the individual who dispensed the drug, and copies must be provided 
to Mylan or designee. 
At the end of the study, Mylan will provide instructions as to disposition of any unused 
investigational product. If Mylan authorizes destruction at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Mylan. Destruction 
must be adequately documented. 
5.5 Masking 
Considering the ophthalmology indication, the term “masking” has been used instead of 
“blinding” throughout the protocol. 
The study drug will be provided as glass vials and syringes.  
Masked personnel 
Confidential
Page 41 of 517

Investigator will be masked throughout the study. Investigator/designee will perform all study 
assessments prior to and following study drug administration. Investigator will also decide on 
the requirement of optional injections as necessary.  
Unmasked Personnel 
If an alternate ophthalmologist is available at the site:  
An alternate ophthalmologist will be identified to be responsible for preparation and 
administration of the study drug. Ophthalmologist administering the study drug will perform 
the post injection procedures like measurement of IOP and any safety assessments up to 
30 minutes after the study drug administration. However, the ophthalmologist administering 
the study drug will not perform any other study assessments including safety and efficacy 
assessments. If the unmasked ophthalmologist is not available at 30 minutes after dosing, the 
masked ophthalmologist may perform post-dose safety assessments. 
An unmasked site personnel, may be identified to be responsible for the receipt, tracking, 
preparation and destruction of study drug. 
If an alternate ophthalmologist is not available at the site; and a qualified unmasked 
Pharmacist or Physician Assistant is available at site: 
Incases, where the site does not have an alternate ophthalmologist, a qualified unmasked 
study personnel, i.e., unmasked pharmacist, physician assistant, will be identified to be 
responsible for the receipt, tracking, preparation and destruction of study drug. The identified 
qualified pharmacist/physician assistant will prepare the drug and hand over the syringe to 
the masked Investigator for intravitreal administration. Every effort should be taken to avoid 
any accidental unmasking of masked study personnel during the process. The detailed 
instructions will be given in a separate masking and unmasking plan.  
Every effort will be made to ensure that all other study site personnel other than those 
designated as unmasked, remain masked to treatment assignment. 
Masked and unmasked roles will be assumed for the entire study and, switching from an 
unmasked to a masked role after the first subject is randomized at a site is not permitted. Any 
deviation to the roles above must be approved by the sponsor, and properly documented 
before any subjects are treated. The Site Signature and Delegation Log are required to be 
maintained as new personnel are added to the study team. 
The central SD-OCT assessment, and central laboratory assessment, including safety, PK and 
immunogenicity, will be performed by the masked personnel. The complete details of the 
study personnel with their masking status will be maintained in the Masking and Unmasking 
plan. 
The responsibilities of the Masked personnel are as follows: 
• Perform all screening procedures up until randomization 
• Assess inclusion/exclusion criteria 
• Obtain medical, surgical, ophthalmic and smoking history 
• Obtain informed consent 
• Collect and process samples for laboratory testing 
• Acquire SD - OCT, fundus photography (FP), and fluorescein angiography (FA) 
images and transfer them to reading centers 
• Acquire ECGs  
• Perform study drug administration (when preparation of study drug is done by an 
identified unmasked pharmacist, physician assistant at the site) 
Confidential
Page 42 of 517

• Perform post-treatment safety assessments (except for post injection procedures like 
measurement of IOP and any safety assessments up to 30 minutes after the study drug 
administration). 
• Decide on need for additional treatment, if any 
• Assess AEs, including severity and relationship 
• Perform complete OE at all study visits 
• Evaluate all safety, including review of images for safety concerns at the site  
• Evaluate vital signs and ECGs; perform physical examinations 
• Test refraction and BCVA 
• Check IOP 
• Assess SD - OCT, FP/FA. 
Responsibilities of the Unmasked Personnel are as follows: 
• Receipt, tracking, and destruction of study drug  
• Prepare study drug 
• Study drug administration and post injection procedures like measurement of IOP and 
any safety assessments up to 30 minutes after the study drug administration (when 
unmasked ophthalmologist is identified at the site) 
Note: For patients in Czech Republic, additionally, the masked or unmasked ophthalmologist 
can monitor the patient for clinical signs and symptoms suggestive of adverse events for at 
least 60 minutes after the study drug administration. 
5.6 Randomization  
Assignment of Subject Identification number (SID), randomization number and study 
medication, as well as site drug inventory control will be managed by an automated IXRS. A 
manual containing complete instructions for Web or telephone access and use will be 
provided to each site prior to study start. At their first clinic visit, the IXRS will assign a SID. 
Each SID will be unique and serve as the primary subject identifier throughout all phases of 
the study. The SID must appear on all CRF pages, source documents, laboratory data, ECG 
and diary data. Subjects qualifying to enter the study drug treatment phase, will be assigned 
an additional “randomization number” by the IXRS at randomization. 
For those patients added to the study as per section 7.1, randomization will be according to 
the original randomization schedule, i.e the next one available will be enrolled, and NOT 
replace the old patients’ treatment. 
5.7 Breaking the Mask 
Regardless of the assigned treatment arm, all subjects in the study are provided with active 
treatment, MYL-1701P or Eylea. 
The masked treatment code must not be broken, except in emergency situations for which the 
identification of the study treatment of a subject is required by the Investigator in case of a 
medical emergency and when the knowledge of the study treatment allocation is required for 
appropriate management of the medical event. Investigator should access the ‘Emergency 
Codebreak’ module in the IXRS system for breaking the mask. The details of the procedure 
for “Emergency Codebreak via Web” are provided in the IXRS User Manual. In such 
situations, the randomization information will be held by designated individual(s), and the 
date and reason for breaking the mask must be recorded. The investigator should follow the 
study’s randomization procedures and should ensure that the code is broken only in 
accordance with the protocol. As the study is masked, the investigator should promptly 
document and explain to the sponsor any premature unmasking (e.g., accidental unmasking, 
Confidential
Page 43 of 517

unmasking due to a serious adverse event) of the investigational product(s). Unmasking of 
treatment code for final data analysis will be done after database lock. Unmasking process 
will be performed in accordance to both Sponsor’s and CRO’s unmasking SOPs, as detailed 
in the statistical analysis plan. 
In the event that the mask is broken for a subject by the Investigator, this subject is to be 
withdrawn from the study. 
5.8 Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to post-
study follow-up) must be recorded with indication, daily dose, frequency, and start and stop 
dates of administration in the CRF. All subjects will be questioned about concomitant 
medication at each clinic visit and at follow up. 
Medications taken within 90 days prior to screening and prior to dosing with study 
medication will be documented as a prior medication. Any other important medications 
relevant to the treatment condition or the study treatment (e.g., prior treatment for DME) 
taken before the 90 days are also recommended to be recorded. 
Medications taken after dosing with study medication will be documented as concomitant 
medications. 
Prohibited Medications 
Subjects will abstain from all prohibited medications as described in Table 2. Use of 
prohibited medication after randomization and during the study will be deemed a protocol 
deviation and such subjects will be assessed by Mylan or designee regarding potential need to 
early terminate study drug (e.g. for safety reasons - see Section 4.3.3). 
Table 2: List of Prohibited Treatment 
• Use of intraocular or periocular corticosteroids or other DME therapy in study eye 
• Antiangiogenic drugs for study eye (e.g., pegaptanib, bevacizumab, ranibizumab, 
aflibercept) 
• Systemic antiangiogenic drugs (e.g., bevacizumab, aflibercept) 
• Drugs that optimize (retinal) microcirculation e.g., calcium dobesilate  
• Pan-retinal or macular laser photocoagulation in the study eye for the treatment of DME 
• Systemic medications known to be toxic to the lens, retina or optic nerve, including 
deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and 
ethambutol 
• Concurrent treatment with an investigational drug or device in the either eye 
• Any other medication/treatment which can impact the visual acuity or safety while on 
concurrent treatment with aflibercept based on Investigator’s discretion. 
Permitted Medication 
Any medication other than the identified prohibited medications that were considered 
necessary for the subject’s best interest and not expected to interfere with the safety or 
efficacy of the study drug can be given at the discretion of the Investigator. Investigator is 
recommended to consult the Medical Monitor if he/she is unclear on the impact of a 
concomitant medication on the study endpoints. 
5.8.1 Study Eye  
Subjects will not be allowed to receive any medications (approved or investigational) for 
their DME in the study eye other than the study treatment (MYL-1701P or Eylea), as 
Confidential
Page 44 of 517

specified in the protocol, until they had completed the end of study (week 52) or early 
termination visit assessments. The prohibited medications should neither be administered 
locally (e.g., IVT, topical, juxtascleral, or periorbital routes), nor systemically, with the intent 
of treating the study eye. 
5.8.2 Fellow / Non-study Eye  
If the fellow eye had DME involving or threatening the center of the macula, requiring 
treatment, standard of care therapy can be administered, if necessary. All fellow eye 
treatments must be recorded on the eCRF as a concomitant medication and/or procedure for 
the fellow eye. The fellow eye will not be considered an additional study eye. Subjects who 
receive treatment for the fellow eye will not be withdrawn from the study. Safety of the 
fellow eye should be monitored, and all AEs collected. Other conditions in the fellow eye 
could be treated with approved therapies. 
Immunogenicity and safety of subjects who received intravitreal anti-VEGF therapy in the 
fellow eye will be analyzed separately and the analysis will be detailed in the statistical 
analysis plan. 
5.8.3 Management of Diabetes 
The subject will receive treatment for diabetes as per standard of care, per institutional 
practice and as prescribed by the treating physician. 
 
Confidential
Page 45 of 517

6 STUDY CONDUCT 
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. A separate PK consent form will be provided to 
the subjects willing to participate in the PK subpopulation at the participating sites. Subjects 
agreeing to participate in the study will sign the ICF and be given a duplicate copy before 
undergoing any screening or pre-screening (if required) procedures. For every subject 
screened, a unique SID will be issued at the time of consent by contacting the IXRS system.  
Once a subject enrolls in this study, the site will make every effort to retain the subject for the 
planned duration of the study. Clinical study site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following. 
• Thorough explanation of the complete clinical study visits schedule and procedural 
requirements during the informed consent process and re-emphasis at each clinic visit 
• A simple explanation of the key data and key time points that are critical for the study's 
successful analysis, and the importance of all the treatment groups to the overall success 
of the study 
• Discussion at screening, and subsequent regular review of possible barriers to clinic visit 
attendance and full study participation and compliance 
• Collection of contact information at screening (address, phone numbers, email), which is 
regularly reviewed at subsequent clinic visits 
• Use of appropriate and timely study visit reminders 
• Immediate and multifaceted follow-up on missed clinic visits, including the possible use 
of trained staff to complete in-person contact with subjects at their homes 
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the CRF. Regardless of 
site plans to support and retain subjects within the study, subjects may voluntarily withdraw 
from the study for any reason and at any time. 
For a subject that completes the study and all procedures, it is anticipated that the duration of 
study would be up to 13 months (56 weeks).  
6.1 Screening Procedures 
Each prospective subject must agree to participate in screening procedures by signing the 
most recent ICF before any screening procedure is initiated. Each subject will be assigned a 
SID via IXRS. The Principal Investigator or Sub-Investigator will review the inclusion and 
exclusion criteria to confirm eligibility of each subject prior to enrolment. 
6.1.1 Screening Visit [Day -28 to Day -1] 
Subjects will commence screening procedures within 28 days prior to randomization, to 
confirm that they meet the selection criteria for the study. If the time between screening 
procedures and potential randomization exceeds 28 days as a result of unexpected delays, 
then the subject’s status will need to be discussed with Mylan or designee to consider 
potential for re-screening (if re screening is agreed, the subject will need to be re-consented 
Confidential
Page 46 of 517

and assigned a new SID via IXRS). Re-screening for other reasons may be possible following 
discussion with the CRO Medical Monitor. If re-screening occurs this will be clearly 
documented within the site file. 
At the Screening Visit, the following procedures will be completed: 
• Written informed consent  
• Medical, surgical, ophthalmic and smoking history, demographics 
• Check study inclusion/exclusion criteria 
• Measure height and weight 
• Serum pregnancy test (if female of child-bearing potential) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Prothrombin time, activated partial thromboplastin time and INR 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Targeted physical examination  
• Record 12-lead ECG 
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
Intraocular pressure (IOP) 
• SD-OCT/CRT (used for eligibility assessment by central reading) 
• Fluorescein Angiography (FA)/Fundus Photography (FP) 
• Review AEs and concomitant medications 
6.2 Treatment phase 
6.2.1 Baseline Visit/Visit 1 (Day 1) 
The following Procedures will be completed: 
• Measure weight 
• Urine pregnancy test (if female of child-bearing potential) 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Targeted physical examination  
• BCVA (confirm eligibility) 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
Intraocular pressure (IOP) 
• SD-OCT/CRT (used for eligibility assessment, based on Investigator assessment 
performed at site) 
• Check study inclusion/exclusion criteria 
• Randomization 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Record 12-lead ECG 
• Study Drug Administration  
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection  
• Review AEs and concomitant medications 
• Issue study diary 
Confidential
Page 47 of 517

6.2.2 Visit 2 (Day 3) 
This visit will be conducted at clinic only for the subjects in sentinel cohort and subjects 
in the pharmacokinetic subgroup; for all other subjects, it will be a telephonic visit.  
For Subjects in Sentinel Cohort, following procedures will be performed: 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• Review study diary 
• Review AEs and concomitant medications 
For Subjects in PK Subgroup, following procedures will be performed: 
• Review study diary 
• Review AEs and concomitant medications 
• Blood sampling for PK 
For the other subjects, telephonic follow up will be done to 
• Review study diary 
• Review AEs and concomitant medications 
6.2.3 Visit 3 (Week 1 ± 2 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Targeted physical examination  
• Record 12-lead ECG 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• Blood Sampling for Immunogenicity 
• Sampling for assessment of drug tolerance or PK  
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Review study diary 
• Review AEs and concomitant medications 
6.2.4 Visit 4 (Week 4 ± 3 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
Confidential
Page 48 of 517

6.2.5 Visit 5 (Week 8 ± 3 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.6 Visit 6 (Week 12 ± 7 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Prothrombin time, activated partial thromboplastin time and INR (For patients in 
Czech Republic only) 
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.7 Visit 7 (Week 16 ± 7 days) 
Visit 7 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
Confidential
Page 49 of 517

• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
Visit 7A (Only for PK subpopulation) 
Additionally, a Visit 7A (2 days after the Visit 7) will be performed for subjects included in 
the PK subpopulation: 
• Blood sampling for PK 
• Review study diary 
• Review AEs and concomitant medications 
6.2.8 Visit 8 (Week 20 ± 7 days)/ Visit 10 (Week 28 ± 7 days)/ Visit 12 (Week 36 ± 7 
days)/Visit 14 (Week 44 ± 7 days)  
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Urine pregnancy test (if female of child-bearing potential) 
• Prothrombin time, activated partial thromboplastin time and INR (Only at Visit 12 
[Week 36 ± 7 days]) [For patients in Czech Republic only] 
• Optional Study Drug Administration (based on Investigator discretion as described in 
Section 5.1.2 
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection (if study drug is administered) 
• Review study diary 
• Review AEs and concomitant medications 
6.2.9 Visit 9 (Week 24 ± 7 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Targeted physical examination  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Prothrombin time, activated partial thromboplastin time and INR (For patients in 
Czech Republic only) 
• Record 12-lead ECG 
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
Confidential
Page 50 of 517

• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.10 Visit 11 (Week 32 ± 7 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.11 Visit 13 (Week 40 ± 7 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity prior to dosing 
• Sampling for assessment of drug tolerance or PK prior to dosing  
• Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration  
• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.12 Visit 15 (Week 48 ± 7 days) 
The following Procedures will be completed: 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT  
• Prothrombin time, activated partial thromboplastin time and INR (For patients in 
Czech Republic only)Urine pregnancy test (if female of child-bearing potential) 
• Study Drug Administration 
Confidential
Page 51 of 517

• Measurement of IOP and assessment of vision by hand movements or counting 
fingers post-injection 
• Review study diary 
• Review AEs and concomitant medications 
6.2.13 Visit 16 (Week 52 ± 7 days) [End of Study Visit] 
The following Procedures will be completed: 
• Measure weight 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Serum pregnancy test (if female of child-bearing potential) 
• Targeted physical examination 
• Record 12-lead ECG 
• BCVA 
• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity 
• Sampling for assessment of drug tolerance or PK 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Fluorescein Angiography/Fundus Photography 
• Review AEs and concomitant medications 
• Collect the study diary 
6.2.14 Early Termination (ET) visit 
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the investigator or sponsor for reasons as 
per Section 4.3.3. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The investigator will contact Mylan or designee in the event that a 
subject fails to complete the study or violates the protocol. 
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic for an ET visit and will have this scheduled as soon as possible after their 
last dose of study drug.  
The following Procedures will be completed: 
• Measure weight 
• Record vital signs – sitting blood pressure, pulse rate and temperature  
• Serum pregnancy test (if female of child-bearing potential) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Targeted physical examination 
• Record 12-lead ECG 
• BCVA 
Confidential
Page 52 of 517

• Complete OE- Slit Lamp examination, Indirect Ophthalmoscopy and measurement of 
IOP 
• SD-OCT/CRT 
• Blood Sampling for Immunogenicity 
• Sampling for assessment of drug tolerance or PK 
• Fluorescein Angiography/Fundus Photography 
• Review AEs and concomitant medications 
• Collect the study diary 
6.3 Treatment Procedures 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The monitor or designee from the 
CRO study team will be informed of these incidents in a timely fashion. 
Activities specific to this protocol are expanded upon further below. 
6.3.1 Efficacy Assessments 
The refractionist and visual acuity examiner, the examiner for the primary outcome 
measurement, for each subject will be masked to the treatment assignment and study eye. 
The subject and ophthalmologist (evaluating Physician) will be masked to whether the 
subject is receiving MYL-1701P or Eylea. 
6.3.1.1 Ophthalmologic Examination 
A study ophthalmologist (evaluating Physician) will perform a dilated eye examination of 
each eye of the subject to establish that the ocular inclusion criteria are met and that none of 
the ocular exclusionary conditions are present.  
Only one eye will be classified as study eye. Study eye will be decided based on BCVA, CRT 
and other eligibility assessments at the discretion of the masked investigator. If both eyes are 
eligible, the study eye will be selected by the principal investigator (masked). Once the study 
eye has been determined, it should remain the study eye throughout. If the fellow eye 
develops DME or if the condition of DME in the fellow eye worsens during the study, the 
fellow eye must not be considered as the study eye.  
The complete OE will include: 
Prior to Study Drug Administration 
Intraocular pressure: 
Intraocular pressure of the study eye will be measured using standard devices (e.g., 
Goldmann applanation tonometry or Tono-pen™). The same method of IOP measurement 
will be used in each subject throughout the study. 
Indirect Ophthalmoscopy: 
Subjects' posterior pole and peripheral retina will be examined by indirect ophthalmoscopy. 
Slit Lamp Biomicroscopy: 
Confidential
Page 53 of 517

Subjects' anterior eye structure and ocular adnexa will be examined using a slit lamp. 
After Study drug administration: 
Finger Counting 
Vision will be assessed post-injection by hand movements or counting fingers. 
Intraocular pressure: 
Intraocular pressure of the study eye will be measured using standard devices (e.g., 
Goldmann applanation tonometry or Tono-pen™). The same method of IOP measurement 
will be used in each subject throughout the study. Intraocular pressure is measured at 
approximately 30 minutes post-dose. 
For Czech Republic, additionally, patient will be monitored by the masked or unmasked 
ophthalmologist for clinical signs and symptoms suggestive of adverse events for at least 60 
minutes after the study drug administration.  
6.3.1.2 BCVA 
Visual acuity of the study eye and fellow eye will be evaluated using the ETDRS protocol at 
4 meters (further detailed in a separate visual acuity testing protocol). 
Refraction and testing of visual acuity to fulfill study eligibility criteria must be performed 
before the subject’s eyes are dilated and before fundus photography and SD-OCT if these 
procedures are to be carried out on the same day. Refraction must precede visual acuity 
testing. A certified Visual Acuity Examiner must perform the standardized, ETDRS visual 
acuity testing. The visual acuity examiner will be masked to the treatment assignment. All 
efforts should be made for the visual acuity examiner to have no knowledge of the study eye 
and have no ready access to the subject’s previous BCVA recorded. 
It is recommended that same Visual Acuity Examiner performs VA throughout the study, 
specifically at baseline and Visit 5 (Week 8). 
A detailed protocol for conducting the VA testing and refraction will be provided as part of 
study procedure manual. 
6.3.1.3 SD-OCT/CRT 
Central retinal thickness and other retinal characteristics will be evaluated at scheduled visits 
using SD-OCT. The CRT will be measured as central subfield thickness. 
An OCT of the study eye and fellow eye will be performed by a certified OCT Technician 
according to the standardized procedures described in separate manual prepared for this 
study. OCT images for the study eye will be transmitted to an independent image reading 
center. All OCT images will be archived electronically at the study sites as part of the source 
documentation. OCT technicians will be certified to maintain quality and consistency. OCT 
technicians will be masked to the study drug assignment. 
At screening, for subject eligibility assessment, CRT will be assessed by central reading of 
SD-OCT images.  
At randomization, for assessment of continued eligibility of the subject, CRT reading by the 
Investigator performed at the site will be used.  
Similarly, for assessment of requirement of additional 4-weekly doses as described in 
Section 5.1.2, the CRT reading by the Investigator performed at the site will be used. 
However, for efficacy analysis the central CRT reading of SD-OCT at all visits will be 
considered. 
Confidential
Page 54 of 517

 
Because the eye must be dilated for OCT, it must be performed after testing visual acuity if 
these procedures are carried out on the same day. 
6.3.1.4 Fluorescein Angiography/ Fundus Photography 
The anatomical state of the retinal vasculature of the study eye and fellow eye will be 
evaluated by FA/FP at the screening visit and end of study visit at Week 52. The FA/FP from 
the screening visit (visit 1) will be captured and transmitted to the central reading center for 
both eyes and reviewed before randomization for eligibility assessment. 
FA/FP images from the end of study visit will be read by the investigator at the site, but the 
images must be transmitted to the central reading center for archival. 
All FA/FP images will be archived electronically at the study sites as a part of source 
documentation. 
Photography must be performed after testing visual acuity if these procedures are to be 
carried out on the same day. Fluorescein Angiography/Fundus Photography will be done after 
other investigations including blood and urine samples are collected to avoid any interference 
from fluorescein. A detailed protocol for image acquisition and transmission will be provided 
in the study procedure manual. 
6.3.2 Safety Testing 
6.3.2.1 Adverse Event Assessment 
If subject reports any symptoms before drug administration, they will be evaluated by 
medical staff and necessary measurements will be performed. The Principal Investigator or 
Medical Sub-Investigator will be notified before dosing to determine the course of action. 
Subjects will be routinely queried regarding the presence or absence of adverse events using 
open ended questions. The clinic will provide documentation of any adverse events in the 
subject’s eCRF. The adverse event source documentation will minimally include the 
following information: date and time of assessment, the outcome of the response, and 
identification of the clinic staff member collecting the information. 
Arterial thromboembolic events following intravitreal use of study drug will be classified 
according to Hicks et al, 2018 by an Independent Cardiovascular Adjudication Committee. 
For any potential allergic reaction after administration of study drug, diagnosis and 
assessment of anaphylaxis will be done using NIAID/FAAN criteria of anaphylaxis; the 
management of anaphylaxis should follow the standard institutional practices 
(Appendix 11.1) 
6.3.2.2 Laboratory Safety 
The following clinical safety laboratory tests will be performed at times defined in the study 
schedules in Section 6.1 and Section 6.2. 
Confidential
Page 55 of 517

Table 3: Laboratory Safety Tests 
Hematology 
Chemistry 
Urinalysis 
Other  
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Neutrophils  
Eosinophils 
Monocytes  
Basophils  
Lymphocytes 
PT 
aPTT 
INR 
HbA1cc  
Urea and Creatinine 
Glucose (non-fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (Bicarbonate) 
AST, ALT 
Total Bilirubin 
Direct/Indirect bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Microscopya 
Serum hCGb 
Urine Pregnancy Test 
(Locally) 
 
a. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase. 
b. At visits, as per study schedule 
c. HbA1c testing will be done at Screening, Baseline, Visit 6 (week 12), Visit 9 (week 24), EOS/ET 
Hematology and chemistry will be analyzed by central laboratory. Urinalysis will be 
conducted by dipstick at site and if urine is positive for blood, protein, nitrites, or leukocyte 
esterase, will be analyzed via microscopy by a central laboratory. 
Additionally, prothrombin time, activated partial thromboplastin time and INR will be done 
at screening. For Czech Republic patients, additional tests of prothrombin time, activated 
partial thromboplastin time and INR will be performed every three months (at Visit 6, 9, 12 
and 15) during the treatment period. 
Blood volumes to be collected and blood and urine sample handling instructions will be 
provided in the central vendor laboratory manual. The central laboratory will provide 
collection materials and directions for packaging and shipment of samples. 
If any blood sample could not be analyzed due to issues in the sample collection, processing 
or shipment, the investigator may repeat the sampling to be analyzed in the central laboratory. 
Any clinically significant findings in laboratory safety data should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.3.2.3 Vital Signs 
Vital signs include BP, pulse rate and temperature. Blood pressure will be measured after the 
subject was sitting for 5 mins. Vital signs will be measured at times specified in Section 6.1 
and Section 6.2. 
Sitting blood pressure will be measured with the subject’s arm supported at the level of the 
heart and recorded to the nearest mmHg after 5 minutes of rest. Where possible, the same arm 
(preferably the dominant arm) will be used throughout the study. 
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time. The use of automated devices for measuring blood 
pressure (BP) and pulse rate are acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds. Any clinically significant 
changes in blood pressure and pulse rate should be recorded as an AE. Determination of 
clinical significance and seriousness will be based on the Investigator's medical judgment. 
Confidential
Page 56 of 517

6.3.2.4 12-lead ECG 
In this study, 12-lead ECGs should be collected at times specified in the study schedule in 
Section 6.1 and Section 6.2.  
To ensure safety of the subjects, a medically qualified individual at the site will assess ECG 
recordings and make any comparisons to baseline measurements. The ECG data (QT interval, 
heart rate [HR], QRS duration, PR and RR interval) will be recorded. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. Any clinically 
significant ECG abnormalities measured at screening should be assessed for their effects on 
subject eligibility of the study and recorded in medical history. Any clinically significant 
changes between the screening and subsequent ECGs should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment. 
6.3.2.5 Targeted Physical Examination 
A targeted physical examination will be performed at time points specified in the study 
schedule in Section 6.1 and Section 6.2. The targeted physical examination will include 
evaluation of the head, eyes, ears, nose and throat. If indicated, based on report of adverse 
events or result of safety laboratory test, directed physical exam of relevant organ systems 
will be performed at additional visits as necessary. 
Any clinically significant finding at Screening Visit should be recorded under medical history 
and changes between Screening Visit and subsequent examinations should be recorded as an 
AE. Determination of clinical s ignificance and seriousness will be based on the investigator's 
medical judgment. 
6.3.3 Pharmacokinetic Assessment  
The PK sampling will be done only in subjects enrolled in the PK subpopulation. The PK 
subpopulation will include at least 32 subjects in each study arm. The PK assessment will be 
performed at time points specified in the study schedule in Table 1 and Section 6.2. 
The blood samples will be analyzed for free aflibercept concentrations using a fully validated 
analytical method.  
The exact time of study drug dosing and PK sample collection will be noted for subjects in 
PK subpopulation.  
6.3.4 Immunogenicity Assessment 
The multi-tiered sample analysis recommendations for immunogenicity testing will be 
employed for the immunogenicity assessment. (FDA 2016; Mire-Sluis AR et al., 2004; 
Shankar G et al., 2008)  
All samples designated for immunogenicity evaluation will undergo a screening assay to 
detect the presence of antidrug antibodies (ADA) against aflibercept. Samples identified as 
positive in the screening assay will then be tested in a confirmatory assay. Confirmed positive 
samples will be further evaluated for antibody titer and the presence of neutralizing 
antibodies against aflibercept.  
Additionally, free aflibercept concentration in all the ADA samples will be determined to 
evaluate drug tolerance status.  
Confidential
Page 57 of 517

Antidrug antibody, neutralizing antibody, and drug concentration analysis will use fully 
validated analytical methods. Bioanalytical methodology and procedures will be documented 
in a sample analysis protocol. 
6.3.5 Blood Volume 
Blood samples will be collected for immunogenicity, drug tolerance and safety laboratory 
investigations as detailed in Study Schedule (Table 1). Additionally, blood samples will be 
collected for PK analysis in the subjects who are part of the PK subpopulation as specified in 
Study Schedule (Table 1).  
6.3.5.1 Immunogenicity Blood Sampling 
Blood samples will be collected for immunogenicity analysis from all subjects at the time 
points presented in the Study Schedule (Table 1). Up to 4 blood samples (5 ml each) will be 
collected at each time point, except for baseline pre-dose time point, where 6 samples (5 ml 
each) will be collected. One sample will be used to determine the presence of ADA against 
aflibercept and 1 sample will be used to determine the presence of neutralizing antibodies 
against aflibercept. The other 2 samples collected will be stored in reserve for potential 
supplemental immunogenicity testing and/or characterization. The additional 2 samples, 
collected at baseline, will be applied for method optimization and validation. The blood 
samples will be collected by direct venipuncture, and the exact time of blood sampling will 
be recorded. Sample handling instructions are specified in the laboratory manual. 
Blood samples will also be collected for drug concentration (drug tolerance) analysis from all 
subjects at the time points presented in the Study Schedule (Table 1). One blood sample of 
4.5 mL will be taken in CTAD plasma tube (buffered citrate, theophylline, adenosine, and 
dipyridamole). The blood samples will be collected by direct venipuncture, and the exact 
time of blood sampling will be recorded. Sample processing and handling instructions are 
specified in the laboratory manual.  
6.3.5.2 Pharmacokinetic Blood Sampling (CTAD Plasma) 
One blood sample of 4.5 mL will be taken into a CTAD plasma tube (buffered citrate, 
theophylline, adenosine, and dipyridamole) at each time point, as outlined in Study Schedule 
(Table 1). Study Conduct Section (Section 6.1 and Section 6.2) provides detailed information 
on each procedure and assessment required for compliance with the protocol.  
The blood samples will be taken by direct venipuncture, and the exact time of blood sampling 
will be recorded. Sample processing and handling instructions are specified in the laboratory 
manual. 
6.3.5.3 Safety Blood Sampling 
The blood samples will be collected at the time points as presented in Study Schedule 
(Table 1). The details of the sample handling and shipment will be provided in a separate 
laboratory manual. 
6.3.5.4 Shipment of Samples 
The shipment details and assay laboratory contact information will be provided to the 
investigator site prior to initiation of the study. 
Confidential
Page 58 of 517

7 STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition and/or its analysis will also be reflected in a protocol amendment. 
7.1 Sample Size Determination 
 
 
 A total of 324 subjects will be randomized 
at 1:1 ratio to each arm after allowing for approximately 10% drop-outs. 
 
 
 
  
 
 
 
 
 
 
 
 Randomization will be stratified by BCVA at baseline (ETDRS Letter Scores 73-
55 vs 54-38) and geographical region (US, Europe, Japan and Rest of the world). 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential
Page 59 of 517

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 Primary Endpoints 
7.2.1 Definition of Primary Endpoints 
The primary efficacy endpoint will be the mean change from baseline in BCVA as assessed 
by ETDRS letters at week 8. 
7.2.2 Statistical Methodology for Primary Endpoints 
The analysis of the primary endpoint will be based on a mixed model repeated measures 
analysis with terms for treatment, visit, treatment by visit interaction, and region, together 
with baseline BCVA as a covariate. The within subject variance-covariance matrix will be 
assumed to be unstructured, estimation will use restricted maximum likelihood, and the 
denominator degrees of freedom will use the Kenward-Roger estimate. This model will 
provide an estimate, standard error, and 90% as well as 95% two-sided CIs for the treatment 
difference at week 8. 
7.2.3 Primary Analysis for Primary Endpoints 
Equivalence will be demonstrated if the CIs for the treatment difference of mean change from 
baseline to week 8 for BCVA are fully contained within the interval (-3, 3). The primary 
analysis will be performed on the Full Analysis Set (FAS) and will include data from all 
visits regardless of whether the subject is still receiving study medication. 
7.2.4 Sensitivity Analyses for Primary Endpoints 
A sensitivity analysis of the primary endpoint will be carried out in which BCVA values after 
discontinuing study medication will be excluded. Supportive analyses of the primary 
endpoint will also be produced based on the per protocol (PP) Population. 
Confidential
Page 60 of 517

Additional sensitivity analyses may be performed to address the impact of missing data due 
to drop-outs. Details will be provided in the SAP. 
7.2.5 Missing Data 
Missing data will not be imputed in the primary analysis of the primary efficacy endpoint. 
Imputation techniques in sensitivity analyses will be described in the SAP. 
In descriptive summaries and listings, no imputation will be employed. 
7.2.6 Sub-Group Analyses 
Subgroup analyses by baseline BCVA, age, gender, race, ethnic origin, and geographic 
region for key efficacy endpoints will be performed. Details will be provided in the SAP. 
7.3 Secondary Endpoints 
7.3.1 Efficacy 
The key secondary efficacy endpoint is 
• The mean change from baseline in CRT as determined by SD-OCT over time 
Only the central CRT reading of all the SD-OCT images across visits will be used for 
efficacy analysis. 
The other secondary efficacy endpoints will include: 
• The mean change in BCVA over time  
• Proportion of subjects who gained ≥15 letters from baseline in BCVA, assessed in 
change from baseline in ETDRS letters over time 
• Number of administrations of study drug required 
The proportion of subjects who gained ≥15 letters from baseline in BCVA at weeks 1, 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 will be presented by treatment. For each time 
point, the summary table will present the number of subjects in each treatment, the 
proportions by treatment, the difference in proportions, and the 95% CI for the difference. 
These estimates will be unadjusted for covariates. 
The number of administrations of study drug required over the treatment period will be 
descriptively summarized. 
The other secondary efficacy endpoints will be analyzed in a similar manner as the primary 
efficacy endpoint. 
All analyses will be performed on the FAS and the PP Population. 
7.3.2 Safety 
Safety will be assessed over time, based on the following evaluations: 
• Ocular (study and fellow eye) and non-ocular adverse events (AE) 
• Vital signs 
• Physical examinations performed 
• Complete OE 
• Safety labs (Serum chemistry, hematology and urinalysis) 
• Twelve-lead ECGs 
The analyses of safety data are described in Section 7.6. 
Confidential
Page 61 of 517

7.3.3 Immunogenicity 
Occurrence, titer, and neutralizing capacity of ADA will be summarized at each scheduled 
sampling time. Subgroup analysis of ADA positive and ADA negative groups on efficacy, 
safety and pharmacokinetic endpoints will be performed. 
7.3.4 Pharmacokinetics 
For all the subjects in the PK subpopulation, concentrations of aflibercept (free drug) will be 
summarized at each scheduled sampling time. 
7.4 Analysis Set Definitions 
The Safety Population will consist of all subjects who received at least 1 dose of study drug. 
Full Analysis Set (FAS) will consist of all randomized subjects who receive any study drug, 
who have a baseline BCVA, and who also have at least one post dosing BCVA assessment. 
Per Protocol (PP) Population will consist of those subjects in the FAS who have no major 
protocol deviations impacting efficacy as further detailed in the Statistical Analysis Plan. 
Assignment to the PP Population will be determined prior to unmasking the study. 
7.5 Interim Analyses 
Interim analysis is not planned for this study. 
7.6 Other Safety Analyses 
Analysis of all safety data will be performed on the Safety Population and will be presented 
by the treatment received.  
Adverse events (both ocular and non-ocular AE) will be coded using latest version of 
Medical Dictionary for Regulatory Authorities (MedDRA). The occurrence of AEs and SAEs 
will be summarized in terms of incidence, as well as in terms of total number of AEs. 
Analysis of AEs in terms of incidence by severity and by relatedness will also be provided.  
Prior and concomitant medications will be coded by the WHO Drug Dictionary Enhanced 
and will be summarized. Medical history will be listed by subject and coded using the latest 
version of MedDRA and will be summarized.  
For intraocular pressure, descriptive statistics at each visit and change from baseline at each 
visit will be provided. Other ophthalmological examinations will be summarized as shift 
tables. Listings will also be provided for each type of safety data. 
7.6.1 Vital Signs 
Blood Pressure and pulse rate will be listed and descriptively summarized (N, mean, standard 
deviation, minimum and maximum) by treatment group and visit. Baseline (defined as the 
pre-dose value collected on Visit 1/Day 1) and changes from baseline will be similarly 
summarized.  
7.6.2 ECG Analyses 
ECG data; QT, QTc (Fridericia’s), heart rate (HR), QRS duration, PR and RR interval will be 
listed. 
Baseline and change from baseline for QT, QTcF, HR, QRS, RR and PR will be summarized 
using descriptive statistics (N, mean, standard deviation, minimum and maximum) by 
treatment and study week. 
Confidential
Page 62 of 517

For QTcF a classification of absolute values and increases from baseline will be performed. 
The number of subjects with maximum absolute QTcF <450 msec, 450 msec ≤QTcF 
<480 msec, 480 msec ≤QTcF <500 msec and QTcF values ≥500 msec will be tabulated by 
treatment and visit. The number of subjects with maximum increase from baseline QTcF 
<30 msec, 30 msec ≤QTcF <60 msec and QTcF ≥60 msec will be tabulated by treatment and 
visit. 
7.6.3 Laboratory Data 
Descriptive summaries of observed values and change from baseline will be presented for 
clinical laboratory evaluations (Serum chemistry and hematology) by treatment group. 
Assessments of laboratory variables according to clinical relevance will be tabulated by visit 
and treatment group for each clinical laboratory parameter in frequency tables. Additionally, 
for each laboratory parameter, shifts in value from baseline to all post-baseline visits will be 
presented by treatment group in shift tables. 
The assessment of categorical urinalysis variables will be tabulated by visit for each urine 
parameter by treatment group in frequency tables. Additionally, for each of the urine 
parameters, shifts in assessments from baseline to all post-baseline visits will be presented for 
each treatment group in shift tables. 
 
Confidential
Page 63 of 517

8 ADMINISTRATIVE PROCEDURES 
8.1 Source Documentation Forms 
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance. 
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into eCRF/database. 
8.2 Access to Data/Source Documentation 
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections. 
8.3 Clinical Study Report and Case Report Forms (CRFs) 
 The CSRs will be provided in 
accordance with the International Conference on Harmonization (ICH) E-3 guidelines 
including Annex I (Synopsis) documenting the clinical execution of the study. The reports 
will include a description of any protocol deviations. The reports will also include reasons for 
withdrawals and any necessary treatment. The reports will include changes in study conduct 
and contingency measures implemented during the restrictions related to the COVID-19 
pandemic. A listing of all participants affected by the COVID-19 related study disruption will 
be included in the CSRs. Analyses and corresponding discussions that address the impact of 
implemented contingency measures on the safety and efficacy results will also be reported in 
the CSRs. The reports will also include tables presenting demographics (separate summary 
tables for enrolled and completed subjects), and adverse events recorded during the study. In 
addition, the clinical study reports will include a Quality Assurance statement, documenting 
that the reports have been reviewed for completeness, accuracy, and compliance with the 
protocol and applicable local and federal regulations. For final clinical reporting purposes 
only, adverse events deemed “definite”, “probable” or “possible” will be included in the 
treatment-related summaries/listings. 
Case report forms (CRFs) containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
Principal Investigator must sign each subject’s CRF after completion of data entry, signifying 
that the data entered in the CRF is complete and accurate. Electronic CRFs may be provided. 
8.4 Adherence to Protocol 
Except for an emergency in which proper care for the protection, safety and well-being of the 
study subjects requires medical treatment, the study will be conducted as described in the 
approved protocol (and amendments, if applicable), GCP, and applicable SOPs. In addition, 
the study will be conducted in accordance with the applicable regulatory requirements of the 
country where the study is being conducted as well as the country where the study will be 
submitted. Any deviation(s) from the protocol will be recorded and presented in the final 
report. Principal investigator should document protocol deviations for all disruptions due to 
COVID-19 pandemic by referring to COVID-19 in the deviation description. 
 
Confidential
Page 64 of 517

8.5 Data Handling and Record Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the study 
subjects remains protected. 
A CRF is required to be completed for each subject receiving study medication. The CRF is 
property of the sponsor and the Investigator must review all CRFs prior to submission to the 
sponsor. 
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. 
The investigator must obtain in writing the sponsor’s agreement to dispose of any records, 
even if the retention period has been reached. 
8.6 Confidentiality 
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee. 
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data. 
8.7 Ethics and Regulatory Authorities 
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH-E6) in addition to the regulatory requirements of the country where the study is 
being conducted as well as the country where the study will be submitted. 
8.7.1 Institutional Review Board/Ethics Committee 
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
consent to the investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the sponsor prior to enrolling any subjects into the study. 
8.7.2 Regulatory Authority 
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to study start. Upon completion, the Regulatory Authorities 
will be notified the study has ended. The study will only be undertaken in compliance with 
the local regulatory requirements. 
Confidential
Page 65 of 517

8.8 Informed Consent 
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document to be used will be submitted by the investigator to an 
independent institutional review board (e.g., IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record. 
8.9 Disclosure and Publication of Clinical Study Data 
The disclosure and publication of clinical study data will be detailed in the clinical study 
agreement with the Investigators. 
8.10 End of Study 
The end of study is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later. 
Confidential
Page 66 of 517

9 ADVERSE EVENT REPORTING 
9.1 Adverse events 
All observed or subject-reported AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as outlined in this section. 
Subjects will be provided a study diary to capture adverse events in between the visits. The 
Investigator/designee will review information recorded in the study diary during the visits. 
Study diary will be collected back from the Subject prior to study completion or early 
termination. 
The Investigator must pursue and obtain information adequate both to determine the outcome 
of all AEs and to assess whether it meets the criteria for classification as an SAE requiring 
immediate notification to Mylan. The Investigator is required to assess causality and should 
obtain sufficient information to determine the causality of all AEs. All AEs will be followed 
until the event is resolved, deemed to be stable, or until the event is found to be due to 
another known cause (concurrent condition or medication) and clinical judgment indicates 
that further evaluation is not warranted with the sponsor concurring with that assessment.  
9.2 Definitions  
9.2.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product. An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with drug administration, whether or not related to the product. 
The above definition covers also cases of  
• Exacerbation of pre-existing diseases or conditions. 
o Pre-existing diseases or conditions will not be considered AEs unless there is 
an increase in the frequency or severity, or a change in the quality of the 
disease or condition.  
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug or drug-food 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent; this should be reported regardless of sequelae. 
 
An AE will be defined as a treatment-emergent adverse event (TEAE) if the first onset (or 
worsening, in the case of pre-existing disease) is after the first administration of MYL-1701P 
or Eylea after randomization through EOS/ET.  
AEs should be categorized as those related to the Study eye, fellow eye and systemic AEs. 
AEs reported from subjects receiving Anti-VEGF treatment in fellow eye will be separately 
reported. 
9.2.2 Adverse Drug Reaction 
All noxious and unintended responses to an investigational product related to any dose of the 
investigation products should be considered adverse drug reactions (ADRs). The phrase 
“responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility. All AEs judged by 
Confidential
Page 67 of 517

either the reporting Investigator or the sponsor as having a reasonable causal relationship to 
an investigational product will be designated as ADRs. 
All AEs, with the causal relationship to the study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.” 
9.2.3 Unexpected Adverse Event/Adverse Drug Reaction 
An unexpected AE or ADR is defined as one whose nature or severity is not consistent with 
the applicable reference safety information designated for the study. For example, hepatic 
necrosis would be unexpected (greater severity) if the IB only listed elevated hepatic 
enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
The reference safety document is the Investigator’s Brochure for MYL-1701P. For Eylea and 
any concomitant medication, the respective SmPC or US prescribing information will be the 
reference safety document. 
9.2.4 Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
o NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it were more 
severe. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly. 
o NOTE: A congenital anomaly in an infant born to a mother who was exposed to 
the study drug during pregnancy is considered an SAE. However, a newly 
diagnosed pregnancy in a subject that has received the study drug is not 
considered an SAE unless it is suspected that the study drug interacted with a 
contraceptive method and led to the pregnancy. The subject with newly diagnosed 
pregnancy will discontinue receiving study treatment and will be followed-up 
every 3 months until delivery or termination to gather information about the 
outcome of the pregnancy.  
• Is an important medical event. 
o NOTE: Important Medical Event: Medical and scientific judgment should be 
exercised in deciding whether it is appropriate to consider other situations serious, 
such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject and / or may 
require intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. 
o For this protocol, any cancer, including localized basal cell carcinoma, is 
considered an important medical event, to be reported as a SAE. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
o NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an 
overnight stay. Events NOT to be reported as SAEs are hospitalizations for the 
following:  
Confidential
Page 68 of 517

 Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition.  
 Treatment, which was elective or pre-planned, for a pre-existing condition 
that is unrelated to the indication under study and did not worsen. 
 Admission to a hospital or other institution for general care due to social or 
economic reasons (e.g., no access to local ambulatory medical care). 
Treatment on an emergency, outpatient basis for an event not fulfilling any 
of the definitions of serious given above and not resulting in hospital 
admission. 
Hospitalization also does not include the following: 
 Rehabilitation facilities 
 Hospice facilities 
 Respite care (e.g., caregiver relief) 
 Skilled nursing facilities 
 Nursing homes 
Any non-serious AE that is determined by the medical monitor/sponsor to be serious (per 
company policy or regulatory requirements) will be communicated to the Investigator for 
reclassification. To assist in the determination of case seriousness further information may be 
requested from the Investigator to provide clarity and understanding of the event in the 
context of the clinical study. 
9.3 Management of Adverse Events 
AEs or SAEs will be collected from the time the subject signs the informed consent form 
until the follow-up visit or 28 days after last dose of study treatment. Pre-existing diseases or 
conditions (reported at visit 1 in medical history) will not be considered as AEs unless there 
is an increase in the frequency or severity, or a change in the quality of the disease or 
condition. An SAE deemed to be related to the study drug by the Investigator in consultation 
with sponsor will be reported even after the Follow-up visit if reported by subjects. 
9.3.1 Collection 
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE, as described previously. At each visit, the subject 
will be allowed time to spontaneously report any issues since the last visit or evaluation. The 
Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions, 
such as 
o “How are you feeling?” 
o “Have you experienced any issues since your last visit?” 
o “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made by the Investigator during the visit will also be 
considered AEs. 
The subject’s diary should also be reviewed at each study visit for adverse events. When 
study diaries are issued, subjects will be appropriately educated by the study designee on 
what constitutes an adverse event and instructed to record adverse events in the study diary in 
a timely manner.  
Confidential
Page 69 of 517

9.3.2 Evaluation 
9.3.2.1 Severity Assessment of Adverse Events 
The clinical severity of an AE will be graded using the NCI-CTCAE Criteria Version 4.03. A 
copy of these criteria will be provided to each study site. If an AE is not listed in the CTCAE, 
its clinical severity will be classified as follows: 
Table 6: Clinical Severity of Adverse Events 
The Investigator will use the terms defined below to describe the maximum intensity of the AE.  
Grade 1 – MILD 
Does not interfere with subject's usual function 
Grade 2 – MODERATE 
Interferes to some extent with subject's usual function 
Grade 3 – SEVERE 
Interferes significantly with subject's usual function 
Grade 4 - LIFE-THREATENING 
Risk of death at time of event 
Grade 5 – DEATH 
Death related to AE 
If an AE is graded 4 or 5 according to the above criteria, then the AE meets the criteria for an 
SAE and the Investigator should immediately notify the sponsor or designee as described in 
Section 9.3.2.8. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of 
intensity based on the CTCAE grading or on the above table, whereas an SAE is an AE that 
meets any of the regulatory specified criteria required for designation as seriousness 
described in Section 9.2.4. 
Confidential
Page 70 of 517

9.3.2.2 Action Taken 
The possible actions taken for an AE are described in Table 7. 
Table 7: Action Taken for an Adverse Event 
Treatment interrupted 
The treatment was temporarily interrupted 
Treatment withdrawn 
The treatment was permanently discontinued 
Unknown 
Not known, not observed, not recorded, or refused 
No action taken 
The AE did not require any intervention 
Not applicable 
AE occurred after study medication was permanently withdrawn or 
subject completed the treatment period 
9.3.2.3 Outcome at the Time of Last Observation 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Sponsor or its 
designated representative. 
• The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
All ongoing AEs without fatal outcome (i.e., did not cause death) will be recorded as not 
recovered/not resolved at the time of death. 
*Only select fatal as an outcome when the AE results in death. If more than one AE is 
possibly related to the subject’s death, the outcome of death should be indicated for the AE 
which is the most plausible cause of death in the opinion of the Investigator.  
Note: although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs.  
9.3.2.4 Causality Assessment of Adverse Events 
For all adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event. The investigator is required to assess causality 
of each AE. 
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. The 
Investigator must make an assessment of the relationship of each AE (serious and 
non-serious) to the study treatment(s) and record this relationship in the CRF. 
In addition, if the Investigator determines an AE or SAE is associated with the protocol 
specified study procedures, the Investigator must record this information about the causal 
relationship in the source documents and CRF, as appropriate, and report the assessment in 
accordance with the reporting requirements, as applicable, AE or SAE. 
Factors that need to be considered when making a causality assessment include: 
• Temporal relationship (e.g., time of onset) 
Confidential
Page 71 of 517

• Clinical and pathological characteristics of the event(s) 
• Pharmacological plausibility 
• Exclusion of confounding factors (medical and medication history) 
• Drug Interactions 
• De-challenge/re-challenge 
• Dose relationship 
A suspected relationship (definite, probable, and possible) between the events and the study 
medication means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. The Investigator is responsible for assessing relationship of AEs to study treatment 
in accordance with the following definitions (Table 8): 
Table 8: Definition of Suspected Relationship between the Events and Study Medication 
DEFINITELY 
Causal relationship is certain 
For Example: the temporal relationship between 
drug exposure and the adverse event (AE) 
onset/course is reasonable, there is a clinically 
compatible response to de-challenge, other causes 
have been eliminated; the event must be definitive 
pharmacologically or phenomenologically, using a 
satisfactory re-challenge procedure if necessary. 
PROBABLY 
High degree of certainty for 
causal relationship 
For Example: the temporal relationship between 
drug exposure and AE onset/course is reasonable, 
there is a clinically compatible response to de-
challenge (re-challenge is not required), and other 
causes have been eliminated or are unlikely. 
POSSIBLY 
Causal relationship is 
uncertain 
For Example: the temporal relationship between 
drug exposure and the AE onset/course is 
reasonable or unknown, de-challenge information 
is either unknown or equivocal, and while other 
potential causes may or may not exist, a causal 
relationship to study drug does not appear probable. 
UNLIKELY 
Not reasonably related 
although a causal relationship 
cannot be ruled out 
For Example: Event or laboratory test abnormality, 
with a time to drug intake that makes a relationship 
improbable (but not impossible), or disease or other 
drugs provide plausible explanations. 
UNRELATED/NOT 
RELATED 
No possible relationship 
The temporal relationship between drug exposure 
and the AE onset/course is unreasonable or 
incompatible, or a causal relationship to study drug 
is impossible. 
 
If the relationship to the study treatment(s) is considered to be unlikely or not 
related/unrelated, an alternative suspected etiology should preferably be provided (e.g., 
concomitant medications, intercurrent condition) wherever applicable and available. 
9.3.2.5 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
CRF with the following information; where appropriate: 
• AE name or term in standard medical terminology 
• When the AE first occurred (start date and time); SAE start date is defined as the date 
the AE became serious 
• When the AE stopped (stop date and time or date and time of last observation if 
ongoing, i.e., recovering or not recovered) 
Confidential
Page 72 of 517

• Severity of the AE 
• Seriousness criteria (hospitalization, death, etc.) 
• Action taken with study medication as a result of AE 
• Outcome 
• Investigator’s opinion regarding the AE relationship to the study treatments 
9.3.2.6 Treatment of Adverse Events 
AEs that occur during the study will be treated, if necessary, by established standards of care. 
If such treatment constitutes a deviation from the protocol, the reason should be documented 
in the CRF; this can include temporary interruption of study treatment. The decision about 
whether the subject may resume the study treatment will be made by the sponsor after 
consultation with the Investigator and/or medical monitor. 
9.3.2.7 Follow-up 
Any AE will be followed-up to a satisfactory resolution, until it becomes stable, or until it can 
be explained by another known cause (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
outcome of an AE must be reported in the subject’s medical record and recorded on the 
appropriate CRF page. 
New information and any important missing information from prior reports on a SAE must be 
provided promptly to the study sponsor. In addition, the Investigator may be requested by 
Mylan/designee to obtain specific additional follow-up information in an expedited fashion. 
The investigator should respond to targeted follow-up requests as soon as possible and no 
later than 48 hours from receipt of the request. 
9.3.2.8 Notification 
For SAEs, the active reporting period to Mylan, begins from the time that the subject 
provides informed consent, which is obtained prior to the subject’s participation in the study, 
i.e., prior to undergoing any study-related procedure and/or receiving investigational product, 
through and including the follow up visit. Should an Investigator be made aware of any SAE 
occurring any time after the active reporting period, the SAE must be promptly reported to 
Mylan only in case of reasonable causality (i.e. suspected ADR). 
The SAE reporting form is to be completed for all serious adverse events, signed by the 
Investigator, and emailed or faxed with supporting documentation (e.g., CRFs, hospital 
records, laboratory reports). Subject identity details (such as but not limited to name or 
clinic/hospital number) must not be visible on SAE forms or any supporting documentation 
provided by the Investigator. These should be “blacked out” and replaced with the site and 
subject’s study identification number on every page. 
At that time of first notification, the Investigator/designee should provide the following 
information via the SAE report form:  
• Protocol number 
• Reporter (study site and Investigator) 
• Subject’s unique identification number  
• Subject’s age 
• Investigational medicinal product 
• Date of first dose of study treatment 
• Date of last dose of study treatment, if applicable 
• SAE term 
Confidential
Page 73 of 517

• The seriousness criteria that were met 
• Investigator’s opinion of the relationship to the study treatment 
• Severity 
• Start and stop (if applicable) of the event (date and time) 
• A brief description of the event, outcome to date, and any actions taken 
• Concomitant medication at onset of the event 
• Relevant past history information 
• Relevant laboratory test findings 
If the initial notification of an SAE is by telephone, within 24 hours of the initial telephone 
notification the Investigator must email the written SAE report form that describes the SAE 
to the Mylan Product Safety and Risk Management department. 
The Investigator may be requested by Mylan to obtain specific additional follow-up 
information in an expedited fashion. This information collected for SAEs is more detailed 
than that captured on the AE CRF. In general, this will include a description of the SAE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Mylan.  
Any missing or additional relevant information concerning the SAE should be provided on a 
follow-up SAE Report Form. Ensure that any additional information requested by the sponsor 
or designee about the event, as outlined above (e.g., hospital reports, autopsy report) is 
provided to the sponsor as soon as it is available. 
Sponsor Contact Information for Immediately Reportable Events 
All SAEs must be notified within 24 hours by email (preferred) or fax to: 
 
 
 
In the event that an electronic acknowledgment is not received within 24 hours for a SAE 
report submitted by email, please forward the report via fax 
 
9.3.2.9 Regulatory Reporting 
All AEs, including suspected serious unexpected AEs will be reported in accordance with 
applicable local regulations. The Investigator is required to comply with applicable 
regulations (including local law and guidance) regarding notification to her/his regulatory 
authorities, ethics committees (ECs) and institutions. 
Suspected unexpected serious adverse reactions (SUSARs), SAEs and other cases required by 
the concerned competent authorities will be reported by the sponsor or the sponsor’s 
representative to all concerned parties within the prescribed timeframe. The sponsor or 
representative will also submit periodic safety reports (for e.g., Development Safety Update 
Reports) as required by international regulations. 
9.4 Special Situations 
The Investigator should report any case of pregnancy within 24 hours via the pregnancy 
report form. Pregnancy exposures must be followed until a final outcome is determined (e.g., 
parturition, spontaneous or scheduled termination). 
Confidential
Page 74 of 517

9.4.1 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation. Women should be instructed to contact the Investigator immediately if 
pregnancy occurs or is suspected. 
Pregnancy testing will be conducted throughout the study, as detailed in the schedule of 
assessments. A woman who is found to be pregnant at the Screening visit will be excluded 
from the study. A woman who becomes pregnant during the study will be immediately 
discontinued from study treatment. Early discontinuation visit assessments should be 
performed as soon as possible after learning of the pregnancy. This information should be 
captured in the pregnancy form and reported to Mylan Product Safety and Risk Management 
within 24 hours from the time of initial knowledge, even if beyond the closure of the clinical 
database.  
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or an SAE. 
A spontaneous abortion is always considered to be a SAE and will be reported to the sponsor 
within 24 hours of knowledge of the event. 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered to be an elective procedure and not an AE, nevertheless, Mylan requests that the 
outcome (e.g., elective termination) be reported within 24 hours and sent as a follow-up on 
the Delivery and Infant Follow-up Form).  
The Investigator is also responsible for following up the pregnancy at 3 monthly intervals 
until delivery or termination, informing the sponsor about its outcome. 
9.4.2 Overdose, Medication Errors and Other Events 
Overdose, per se of either study treatment or a concomitant medication will not be reported as 
an AE; unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Signs, symptoms, and clinical sequelae associated with intentional overdose are to be 
recorded on the AE CRF page. Dosing and other medication errors are to be recorded as 
protocol deviations. 
9.4.3 Worsening of diabetic macular edema 
Medical occurrences or symptoms of deterioration that are anticipated as part of the normal 
progression of DME of the study eye should be recorded as an AE only if judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in nature at 
any time during the study.  
When recording an unanticipated worsening of study eye DME on the Adverse Event eCRF, 
it is important to convey the concept that the condition has changed by including applicable 
descriptors (e.g., “accelerated DME”). Events that are clearly consistent with the expected 
pattern of progression of the underlying disease should not be recorded as AEs. In cases of 
ocular inflammation, diagnoses terms like iritis, iridocyclitis, vitritis, endophthalmitis or 
uveitis should be used. 
9.5 Abnormal Test Findings  
Abnormal laboratory findings per se (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., ECG, X-rays, and vital signs) are not reported as AEs. However, abnormal 
findings that are deemed clinically significant or are associated with signs and/or symptoms 
must be recorded as AEs if they meet the definition of an AE (and recorded as an SAE if they 
Confidential
Page 75 of 517

meet the criteria of being serious). Clinically significant abnormal laboratory or other 
abnormal findings that are detected after study drug administration or that are present at 
baseline and worsen following the administration of study drug are included as AEs (and 
SAEs, if serious). The Investigator should exercise his or her medical judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Broad guidance for determining whether an abnormal objective test finding 
should be reported as an AE follows:  
• The test result is associated with accompanying symptoms and/or 
• The test result requires additional diagnostic testing or medical/surgical intervention 
and/or 
• The test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, additional concomitant drug 
treatment, or other therapy; and/or 
• The test result is considered to be an AE by the Investigator or sponsor. 
 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE. 
Any abnormal test result determined by retest to be an error does not require reporting as an 
AE. 
 
Confidential
Page 76 of 517

10 REFERENCE LIST 
1. Eylea® [Prescribing Information]. Tarrytown, NY: Regeneron Pharmaceuticals; 2017. 
2. Eylea SPC. Leverkusen, Germany. Bayer AG; Jul 2017. 
3. Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of 
the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011; 94(3): 
311-321.  
4. Ding J, Wong TY. Current Epidemiology of Diabetic Retinopathy and Diabetic 
Macular Edema. Curr Diab Rep. 2012; 12 (4): 346-354. 
5. EMA. Eylea Assessment Report EMA/430291/2014; 2014. 
6. Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. Anti-vascular 
endothelial growth factor for diabetic macular oedema: a network meta-analysis. 
Cochrane Database of Systematic Reviews. 2017; 6: CD007419. DOI: 
10.1002/14651858.CD007419.pub5. 
7. EMA. Guideline on similar biological medicinal products containing Biotechnology-
derived proteins as active substance: Non-clinical and clinical issues. 
EMEA/CHMP/BMWP/42832/2005 (Rev. 1) 18 December 2014, effective 01 July 
2015.  
8. FDA. Guidance for Industry: Scientific considerations in demonstrating biosimilarity 
to a reference product. US FDA, April 2015. 
9. Regeneron Pharmaceuticals, Clinical Study Report Protocol VGFT-OD-1009 
(VISTA), 02 October 2013. 
10. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for 
neovascular age-related macular degeneration. New England Journal of Medicine. 
2011; 364 (20): 1897-1908. 
11. Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs 
intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical 
trial' Journal of the American Medical Association. 2015; 314 (20): 2137-2146. 
12. Prunte C, Fajnkuchen F, Mahmood S. et al. Ranibizumab 0.5 mg treat-and-extend 
regimen for diabetic macular oedema: the RETAIN study. The British journal of 
ophthalmology. 2016; 100(6): 787-95. 
13. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to 
treat neovascular age-related macular degeneration: one-year findings from the IVAN 
randomized trial. Ophthalmology. 2012; 119(7): 1399-411. 
14. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal Aflibercept for Diabetic 
Macular Edema. Ophthalmology. 2014; 121: 2247–2254 
15. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for Neovascular Age-Related 
Macular Degeneration, N. Engl. J. Med. 2006; 355: 1419-1431. 
16. Heier JS, Brown DM, Chong V, et al. Intravitreal Aflibercept (VEGF Trap-Eye) in 
Wet Age-Related Macular Degeneration. Ophthalmology. 2012; 119: 2537-2548. 
Confidential
Page 77 of 517

17. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab 
for Diabetic Macular Edema. N. Engl. J. Med. 2015; 1193-1203 
18. Kaiser PK. Prospective evaluation of visual acuity assessment: a comparison of 
snellen versus ETDRS charts in clinical practice (An AOS Thesis). Trans Am 
Ophthalmol Soc. 2009; 107:311-24. 
19. Dugel PU, Hillenkamp J., Sivaprasad S, et al. Baseline visual acuity strongly predicts 
visual acuity gain in patients with diabetic macular edema following antivascular 
endothelial growth factor treatment across trials. Clin Ophthalmol. 2016; 10:1103-10. 
20. Mire-Sluis AR, Barrett YC, Devanarayan V, et al. Recommendations for the design 
and optimization of immunoassays used in the detection of host antibodies against 
biotechnology products. J Immunol Methods. 2004; 289: 1-16. 
21. Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation 
of immunoassays used for detection of host antibodies against biotechnology 
products. J Pharm Biomed Anal. 2008; 48(5): 1267-81. 
22. Food and Drug Administration (FDA). Guidance for Industry: Assay Development 
and Validation for Immunogenicity Testing of Therapeutic Protein Products 2016, 
U.S. Department of Health and Human Services. 
23. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: Summary report—Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
24. Karen A. Hicks, et al, on behalf of the Standardized Data Collection for 
Cardiovascular Trials Initiative (SCTI), 2017 cardiovascular and stroke endpoint 
definitions for clinical trials, Journal Of The American College Of Cardiology, 
published jointly by the American College of Cardiology Foundation And American 
Heart Association, INC. 2018 71(9).1021-1034. 
 
Confidential
Page 78 of 517

11 APPENDIX. 
11.1 
Appendix: NIAID / FAAN clinical criteria for diagnosis and assessment of 
Anaphylaxis (Sampson et al., 2006) 
Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of skin, mucosal tissue 
or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT 
LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence) 
2. Two (or more) of the following that occurred rapidly (minutes to several hours) after 
exposure to a likely allergen for that patient: 
a. Involvement of the skin or mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d. Persistent GI symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to a known allergen for that patient (minutes to several hours): 
a. Infants and Children: Low systolic BP (age specific), or greater than 30% decrease 
in systolic BP 
b. Adults: Systolic BP of less than 90 mmHg, or greater than 30% decrease from 
baseline 
PEF- Peak expiratory flow; BP- blood pressure 
 
 
Confidential
Page 79 of 517

The clinical spectrum of Allergic Manifestations 
 
Confidential
Page 80 of 517