Clinical trial NCT02712008
Conditions: Diabetic Macular Edema
Sponsor: Regeneron Pharmaceuticals
Start date: 2016-03-02; Completion date: 2017-07-10
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study was to compare the efficacy of intravitreal (IVT)-administered REGN910-3 compared to intravitreal aflibercept injection (IAI) in improving best corrected visual acuity (BCVA) in participants with diabetic macular edema (DME).

Detailed description:

Arms: arm 1: Participants were administered intravitreal injection of REGN910-3 (3 milligram (mg):2 mg) every 4 weeks (Q4) on Day 1, Week 4, and Week 8 for 3 initial doses followed by every Week 8 (Q8) dosing beginning at Week 16 up to Week 32. arm 2: Participants were administered intravitreal injection of REGN910-3 (6 mg:2 mg) Q4 on Day 1, Week 4 and Week 8 for 3 initial doses up to week 12. arm 3: Participants were administered intravitreal injection of Aflibercept (IAI) 2 mg Q4 on Day 1, Week 4 and Week 8 for 3 initial doses up to Week 12. arm 4: Participants were administered intravitreal injection of REGN910-3 (6 mg:2 mg) Q4 on Day 1, Week 4 and Week 8 for 3 initial doses. At Week 12, participants were re-randomized to receive REGN910-3 (6 mg:2 mg) at Week 16 and Q8 through Week 32. arm 5: Participants were administered intravitreal injection of REGN910-3 (6 mg:2 mg) Q4 on Day 1, Week 4 and Week 8 for 3 initial doses. At week 12, participants were re-randomized to receive REGN910-3 (6 mg:2 mg) at Week 20 and Q12 through Week 32. arm 6: Participants were administered intravitreal injection of Aflibercept (IAI) 2 mg Q4 on Day 1, Week 4 and Week 8 for 3 initial doses up to Week 12. At Week 12, participants were re-randomized to receive IAI at Week16 and Q8 through Week 32. arm 7: Participants were administered intravitreal injection of Aflibercept (IAI) 2 mg Q4 on Day 1, Week 4 and Week 8 for 3 initial doses up to Week 12. At Week 12, participants were re-randomized to receive IAI at Week 20 and Q12 through Week 32. arm 8: Participants were administered intravitreal injection of Aflibercept (IAI) 2 mg Q4 on Day 1, Week 4 and Week 8 for 3 initial doses up to Week 12. At week 12, participants were re-randomized to receive REGN910-3 (6 mg:2 mg) at week 16 and Q8 through week 32.
Interventions: intervention 1: REGN910-3 intervention 2: Intravitreal Aflibercept Injection (IAI)
Intervention descriptions: intervention 1: Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept) intervention 2: None

Protocol documents:
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SAP_001.pdf: 
Page 1 of 40 
STATISTICAL ANALYSIS PLAN 
FINAL 
Title:
A Randomized, Double-Masked, Active-Controlled Phase 2 Study of the 
Efficacy, Safety, and Tolerability of Repeated Doses of Intravitreal 
REGN910-3 in Patients with Diabetic Macular Edema
Protocol:
R910-3-DME-1518.03; 31 May 2017
Phase:
2
Sponsor:
Regeneron Pharmaceuticals, Inc.
Date:
October 12, 2017
Author’s Name:
See appended electronic signature page 
  
Approved by:
See appended electronic signature page 
Approved by:
See appended electronic signature page 
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NCT02712008


Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017 
Page 2 of 40 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Background and Rationale ............................................................................................7 
1.2. 
Study Objectives ...........................................................................................................7 
1.2.1. 
Primary Objective .........................................................................................................7 
1.2.2. 
Secondary Objectives ...................................................................................................8 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ..................................8 
2. 
INVESTIGATIONAL PLAN .......................................................................................8 
2.1. 
Study Design and Randomization ................................................................................8 
2.2. 
Sample Size and Power Considerations .....................................................................10 
3. 
ANALYSIS POPULATIONS ....................................................................................11 
3.1. 
Safety Analysis Set (SAF) ..........................................................................................11 
3.2. 
Full analysis set (FAS)................................................................................................11 
3.3. 
Anti-Drug Antibody (ADA) Analysis Set ..................................................................11 
3.4. 
“FAS Secondary Randomization” set .........................................................................11 
3.5. 
“SAF Secondary Randomization” set .........................................................................11 
3.6. 
Pharmacokinetic Analysis Set ....................................................................................12 
4. 
ANALYSIS VARIABLES .........................................................................................12 
4.1. 
Demographic, Baseline Characteristics, and Medical History ...................................12 
4.2. 
Compliance, Exposure, and Additional Treatment .....................................................13 
4.3. 
Prior/Concomitant Medication Variables ...................................................................14 
4.4. 
Efficacy Variables ......................................................................................................14 
4.4.1. 
Primary Efficacy Variable ..........................................................................................14 
4.4.2. 
Secondary Efficacy Variables .....................................................................................14 
4.4.3. 
Additional Efficacy Variables ....................................................................................14 
4.5. 
Safety Variables ..........................................................................................................15 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................15 
4.5.2. 
Surgeries .....................................................................................................................16 
4.5.3. 
Laboratory Safety Variables .......................................................................................16 
4.5.4. 
Ocular Safety Measures ..............................................................................................16 
4.5.5. 
Electrocardiogram .......................................................................................................17 
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017 
Page 3 of 40 
4.5.6. 
Vital Signs ..................................................................................................................17 
4.5.7. 
Immunogenicity ..........................................................................................................17 
4.5.8. 
Pharmacokinetic Variables .........................................................................................17 
5. 
STATISTICAL METHODS .......................................................................................18 
5.1. 
Demographics, Baseline Characteristics, Medical History, and 
Prior/Concomitant Medication ...................................................................................18 
5.2. 
Patient Disposition ......................................................................................................18 
5.3. 
Compliance, Exposure, and Additional Treatment .....................................................19 
5.4. 
Efficacy Analyses .......................................................................................................19 
5.4.1. 
Analysis of Efficacy Variables ...................................................................................19 
5.4.1.1. 
Primary Analysis of Primary Efficacy Variable .........................................................19 
5.4.1.2. 
Sensitivity Analyses of Primary Efficacy Variable ....................................................20 
5.4.2. 
Analysis of Secondary Efficacy Variables .................................................................21 
5.4.2.1. 
Analyses of Continuous Secondary Efficacy Variable ...............................................21 
5.4.2.2. 
Analyses of Categorical Secondary Efficacy Variable ...............................................21 
5.4.3. 
Analysis of Additional Efficacy Variables .................................................................21 
5.4.3.1. 
Analyses of Continuous Additional Efficacy Variables .............................................21 
5.4.3.2. 
Analyses of Categorical Additional Efficacy Variables .............................................21 
5.4.3.3. 
Analyses of Time-to event Additional Efficacy Variables .........................................22 
5.4.4. 
Additional Analysis due to IVRS Dosing Error .........................................................22 
5.5. 
Analysis of Safety Data ..............................................................................................22 
5.5.1. 
Adverse Events ...........................................................................................................23 
5.5.2. 
Surgeries .....................................................................................................................23 
5.5.3. 
Clinical Laboratory .....................................................................................................24 
5.5.4. 
Vital Signs ..................................................................................................................24 
5.5.5. 
Ocular Safety Measures ..............................................................................................24 
5.5.6. 
Electrocardiogram .......................................................................................................24 
5.5.7. 
Analysis of Drug Concentration Data .........................................................................24 
5.5.8. 
Immunogenicity ..........................................................................................................24 
6. 
DATA CONVENTIONS ............................................................................................25 
6.1. 
Definition of Baseline .................................................................................................25 
6.2. 
Handling of Missing Data ...........................................................................................25 
6.3. 
Unscheduled Assessments ..........................................................................................25 
&21),'(17,$/
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7. 
INTERIM ANALYSIS ...............................................................................................26 
8. 
SOFTWARE ...............................................................................................................26 
9. 
REFERENCES ...........................................................................................................26 
10. 
APPENDIX.................................................................................................................27 
10.1. 
Schedule of Events .....................................................................................................27 
10.2. 
Summary of Statistical Analyses ................................................................................30 
10.3. 
Detailed Definition of Selected Subgroups ................................................................32 
10.3.1. 
Hypertension ...............................................................................................................32 
10.3.2. 
Intraocular Inflammation ............................................................................................34 
10.4. 
Criteria for Predefined Lab Abnormalities .................................................................36 
10.5. 
Calculation of Confidence Intervals using Mantel-Haenszel Weighting 
Scheme ........................................................................................................................38 
10.6. 
Detailed Definition of Specific Baseline Assessments ...............................................39 
10.6.1. 
Prior intravitreal anti-VEGF .......................................................................................39 
10.6.2. 
Prior intravitreal steroids ............................................................................................39 
10.6.3. 
Prior focal or grid laser ...............................................................................................39 
10.7. 
Steps for EDTRS Diabetic Retinopathy Severity Scale .............................................40 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram .....................................................................................................8 
Figure 2: 
Study Flow Figure ........................................................................................................9 
Figure 3: 
Dosing Schedule .........................................................................................................10 
&21),'(17,$/
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LIST OF ABBREVIATIONS 
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine Aminotransferase
AMD
Age-related macular degeneration
Ang2
Angiopoietin 2
ANCOVA
Analysis of covariance
APTC
Adjudicated Anti-platelet trialists’ collaboration
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under curve
BCVA
Best corrected visual acuity
BMI
Body mass index
BUN
Blood urea nitrogen
CMH
Cochran-Mantel-Haenszel
CNV
Choroidal neovascularization
CPK
Creatine phosphokinase
CRF
Case report form (electronic or paper)
CST
Central subfield retinal thickness
DME
Diabetic macular edema
DNA
Deoxyribonucleic acid
DR
Diabetic retinopathy 
DRIL
Disorganization of Retinal Inner Layers
DRSS
Diabetic Retinopathy Severity Scale 
ECG
Electrocardiogram
ETDRS
Early treatment diabetic retinopathy study
FA
Fluorescein angiography
FAS
Full analysis set
FDA
Food and Drug Administration
FP
Fundus photography
HbA1C
Hemoglobin A1C
&21),'(17,$/
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IAI
Intravitreal aflibercept injection
ICF
Informed consent form
ICH
International Conference on Harmonization
IOP
Intraocular pressure
IV
Intravenous
IVT
Intravitreal
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
(MedDRA) HLT
High Level Term
(MedDRA) LLT
Low Level Term
(MedDRA) PT
Preferred term
(MedDRA) SOC
System organ class
MI
Multiple imputation
OC
Observed case
OCT
Optical coherence tomography
PCSV
Potentially clinically significant value
PK
Pharmacokinetic
RBC
Red blood cell
Regeneron
Regeneron Pharmaceuticals, Inc.
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
TEAE
Treatment-emergent adverse event
UPCR
Urine Protein Creatinine Ratio 
VA
Visual acuity
VEGF
Vascular endothelial growth factor
WBC
White blood cell
&21),'(17,$/
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1.
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for analysis of the study prior to the database lock. 
The statistical evaluation will be performed according to the specifications given in the protocol 
and, and if applicable, the corresponding amendments. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
technique to be used for the analysis of the REGN910-3-DME-1518 study. The statistical 
analysis of all data will be performed after all patients have either discontinued or completed the 
study at Week 36 (End of Study). 
1.1.
Background and Rationale 
Diabetic retinopathy (DR) is a major cause of visual impairment in the United States. Diabetic 
macular edema (DME) is a manifestation of DR and is the most frequent cause of blindness in 
young and mid-aged adults. Anti-vascular endothelial growth factor (VEGF) therapy has become 
the standard of care treatment for DME. The efficacy and safety of intravitreal aflibercept 
injection (IAI) in this patient population is well characterized. However, in DME there is the 
possibility of improving treatment outcomes. 
Like VEGF, Ang2 expression is upregulated by hypoxia and exposure to elevated glucose levels, 
and ocular levels of both Ang2 and VEGF are elevated in the eyes of humans afflicted with wet 
age-related macular degeneration (AMD) or ischemic retinopathies, including retinopathy of 
prematurity and diabetic retinopathy. In addition, a growing body of experimental evidence 
indicates that not only are VEGF and Ang2 co-regulated in these disease states, but that they 
may also act together to promote pathological neovascularization and vascular permeability.  
These observations together indicate that not only would pharmacological inhibition of Ang2 be 
likely to provide therapeutic benefit in the treatment of diabetic eye disease, but that combined 
inhibition of Ang2 and VEGF could produce a greater therapeutic effect than inhibition of either 
angiogenic factor alone. 
In addition to improving visual outcomes, targeting both the VEGF and Ang-2 pathways in 
neovascular and ischemic eye disease also has the possibility of providing a longer duration of 
action resulting in a longer treatment interval. 
 
REGN910-3 is a co-formulation of REGN910 (anti-Ang2 antibody, nesvacumab) and REGN3 
(anti-VEGF; also called aflibercept). 
1.2.
Study Objectives 
1.2.1.
Primary Objective 
The primary objective of the study is to compare the efficacy of IVT-administered REGN910-3 
compared to IAI in improving best corrected visual acuity (BCVA) in patients with DME. 
&21),'(17,$/
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1.2.2.
Secondary Objectives 
The secondary objectives of the study are to assess: 
x
If REGN910-3 demonstrates an anatomic benefit compared to IAI alone  
x
The duration of effect of REGN910-3 following 3 initial monthly injections 
x
The safety and tolerability of REGN910-3 
x
The presence of anti-REGN910 and anti-aflibercept antibodies in serum  
1.2.3.
Modifications from the Statistical Section in the Final Protocol 
Not applicable 
2.
INVESTIGATIONAL PLAN 
2.1.
Study Design and Randomization 
This is a randomized, double-masked, active-controlled phase 2, multi-center study of the 
efficacy and safety of repeated doses of IVT REGN910-3 versus IAI alone in patients with 
DME. 
The study consists of a screening/baseline period, a treatment period, and an end of study/early 
termination visit (see Figure 1). 
Figure 1: 
Study Flow Diagram 
Screening
Treatment Period
End of 
Study/ET**
Baseline
Re-randomization*
End of Treatment
End of Study
(Day –21)
(Day –1)
(Day 1)
(Week 12)
(Week 32)
(Week 36)
*Patients in group 2 (REGN910-3 high-dose) and group 3 (IAI only) 
**ET = Early Termination 
Eligible patients will be randomized in a 1:2:3 ratio to receive low-dose (3mg:2mg) REGN910-3 
(group 1), high-dose (6 mg:2mg) REGN910-3 (group 2), or 2 mg IAI alone (group 3) (see 
Figure 2).  
At week 12, patients in group 1 will continue to receive REGN910-3 (low-dose) Q8 beginning at 
week 16, with sham injections at non-treatment visits (see Figure 3).
At week 12, patients in groups 2 and 3 will be re-randomized, and stratified by BCVA (using 
4 strata reflecting change in BCVA [Early Treatment Diabetic Retinopathy Study (ETDRS) 
letters] from baseline to week 12: <5 letters, 5≤ BCVA <10 letters, 10≤ BCVA <15 letters, and 
BCVA ≥15 letters).  Please note that the first stratum has been divided into two substrata: 
BCVA≤-20 and -20<BCVA<5 letters during the ongoing study in order to minimize potential 
imbalance for this stratum among treatment groups. 
&21),'(17,$/
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Patients in group 2 will be re-randomized into 2 groups, with dosing from week 16 through week 
32 as indicated: 
x
Group 2a: REGN910-3 high-dose (6 mg:2 mg) Q8 beginning at week 16, with sham 
injections at non-treatment visits 
x
Group 2b: REGN910-3 high-dose (6 mg:2 mg) every 12 weeks (Q12) beginning at 
week 20, with sham injections at non-treatment visits 
Patients in group 3 will be re-randomized into 3 groups, with dosing from week 16 through week 
32 as indicated: 
x
Group 3a: IAI 2 mg Q8 beginning at week 16, with sham injections at non-treatment 
visits 
x
Group 3b: IAI 2 mg Q12 beginning at week 20, with sham injections at non-treatment 
visits 
x
Group 3c: REGN910-3 high-dose (6 mg:2 mg) Q8 beginning at week 16, with sham 
injections at non-treatment visits 
Figure 2: 
Study Flow Figure 
1 Stratification for re-randomization will be based on VA outcomes at week 12 
&21),'(17,$/
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Figure 3: 
Dosing Schedule 
If in the investigator’s judgement, the patient cannot adhere to the protocol-specified dosing 
interval due to persistent or worsening disease and requires an interim injection, the patient may 
receive additional treatment. Patients will receive IAI 2 mg if it is determined that additional 
treatment will be administered. Patients who qualify for additional treatment will continue to 
receive their randomized treatment at future visits. 
The study event table is presented in Appendix 10.1. 
2.2.
Sample Size and Power Considerations 
The sample size calculation is based on the change from baseline in BCVA by ETDRS letter 
score at week 12 in 2 comparisons: 3 mg:2 mg REGN910-3 (group 1) versus 2 mg IAI alone 
(group 3), and 6 mg:2 mg REGN910-3 (group 2) versus 2 mg IAI alone (group 3).  The sample 
size was also determined based on the planned re-randomization of groups 2 and 3 at week 12.  
Assuming that the change in BCVA at week 12 compared to baseline is normally distributed, a 
true difference in the mean change of BCVA of 5 letters and an expected standard deviation (SD) 
of 9.5 letters for each group comparison of REGN910-3 and IAI, a sample size of 39 patients in 
group 1 (3 mg:2 mg REGN910-3), 78 patients in group 2 (6 mg: 2 mg REGN910-3), and 
117 patients in group 3 (2 mg IAI alone) will be needed to provide at least 80% probability that 
95% confidence intervals will exclude 0.  The assumption of the mean (SD) difference between 
groups 1 and 2 is based on the results from completed DME studies (VIVID and VISTA). 
A drop-out rate of approximately 20% was considered, resulting in 50, 100, and 150 patients for 
groups 1, 2, and 3, respectively. 
The sample size was computed using the 2-group Satterthwaite (Moser 1989) t-test of unequal 
sample size of ratio at 1:2:3 by clinical assumption with equal variances using the commercial 
software nQuery Advisor 7.0. 
&21),'(17,$/
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3.
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations of analysis will be used 
for statistical analysis as described below. 
3.1.
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all patients who received any study treatment; analyses on 
the SAF will be based on the treatment actually received (as treated). 
The “as-treated” assignment will only differ from the “as randomized” if the patient is 
systematically (more than 50% of the given treatments) receiving as their primary therapy the 
treatment from an alternative treatment group. Patients whose “as treated” assignment differs 
from their “as randomized” assignment will be listed. 
Treatment compliance/administration at Week 12 and safety analyses for adverse events, 
Intraocular pressure (IOP), and surgeries through Week 36 will be analyzed using the SAF. 
3.2.
Full analysis set (FAS) 
The full analysis set (FAS) will include all randomized patients who received any study 
treatment, have a baseline measurement of BCVA, and at least 1 post-baseline assessment of 
BCVA.  
The FAS will be used to evaluate all efficacy variables at Week 12.  The analysis on the FAS 
will be performed according to the treatment assigned at baseline (as randomized). 
3.3.
Anti-Drug Antibody (ADA) Analysis Set  
The ADA analysis set will include all treated patients who received any study drug and who had 
a reportable result for ADA following the first dose of study drug. ADA analysis will be based 
on all treatments actually received (as treated). 
3.4.
“FAS Secondary Randomization” set
This set will include all the patients in FAS who had completed the study through week 12, had 
received any study treatment after secondary randomization (for patients in group 2-high dose 
and group 3-IAI) or after Week 12 (for patients in group 1-low dose), had assessment of BCVA 
at Week 12, and had at least 1 post-Week 16 assessment of BCVA.  The analysis on the “FAS 
Secondary Randomization” will be performed according to the treatment assigned (as 
randomized) at Week 12 for group 2 and 3 (high dose and IAI, respectively) or at baseline for 
group 1 (low dose). 
For efficacy analyses after Week 12, “FAS Secondary Randomization” will be used.
3.5.
“SAF Secondary Randomization” set
This set will include all the patients in SAF who had completed the study through week 12, had 
received any study treatment after secondary randomization (for patients in group 2-high dose 
and group 3-IAI) or after Week 12 (for patients in group 1-low dose).  The analysis on the “SAF 
&21),'(17,$/
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Secondary Randomization” will be performed according to the treatment assigned (as 
randomized) at Week 12 for group 2 and 3 (high dose and IAI, respectively) or at baseline for 
group 1 (low dose). 
For treatment compliance/administration and all safety analyses through Week 36, “SAF 
Secondary Randomization” will be used.
3.6.
Pharmacokinetic Analysis Set 
The pharmacokinetic (PK) population includes all treated patients who received any study drug 
and who had at least 1 non-missing result for drug concentration following the first dose of study 
drug. 
4.
ANALYSIS VARIABLES 
4.1.
Demographic, Baseline Characteristics, and Medical History 
Demographic and baseline assessments to be summarized will include: 
x
Age, gender, and race 
x
Weight, height, and body mass index (BMI) 
x
Vital signs (baseline heart rate, systolic blood pressure, diastolic blood pressure, and 
temperature) 
x
Hemoglobin A1C (HbA1C) 
x
Duration of Diabetes (years): defined as time from diagnosis (based on medical 
history data (MedDRA HLT “diabetes mellitus”) to randomization
x
Diabetes Type (Type 1 and Type 2) 
x
Intraocular pressure (IOP) 
x
Medical history 
x
Previous treatment for DME  
x
Prior intravitreal anti-VEGF 
x
Prior intravitreal steroids 
x
Prior focal or grid laser 
x
Baseline BCVA 
x
Baseline central subfield retinal thickness (CST) 
x
Baseline Diabetic Retinopathy Severity Score (DRSS) by level 
x
Presence of Disorganization of Retinal Inner Layers (DRIL) 
Medical history will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0. 
&21),'(17,$/
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Prior intravitreal anti-VEGF, Prior intravitreal steroids, and Prior focal or grid laser are defined 
in Appendix 10.6.
4.2.
Compliance, Exposure, and Additional Treatment 
Compliance  
Per patient, compliance with protocol-defined study medication during the 2 time periods 
(12 weeks and 36 weeks) will be calculated for the study eye as follows: 
Treatment Compliance = (Number of received REGN910-3/IAI injections through time 
period/(Number of planned REGN910-3/IAI injections during period of participation in the 
study through time period) x 100% 
For patients who discontinue early, the number of planned injections will be included up to the 
last visit before dropout.
Exposure  
Exposure to study drug will be analyzed for each patient.  The following variables will be listed 
and summarized: 
x
Total number of planned REGN910-3/IAI doses administered. REGN910-3 and IAI 
doses will be summarized separately if patients switch to the other treatment.  
x
Treatment duration of REGN910-3/ IAI: [last treatment date] – [first dose date] + 
28 days (28 days are added, because of the minimum 4-week dosing interval in the 
study) 
Additional Treatment 
Beginning at Week 12, if, in the investigator’s judgement, the patient cannot adhere to the 
protocol-specified dosing interval due to persistent or worsening disease and requires an interim 
injection, the patient may receive additional treatment. Patients will receive IAI 2 mg if it is 
determined that additional treatment will be administered.  Additional treatment will be 
summarized as follows: 
x
Total number of patients that received additional treatment by treatment group 
x
Total number of injection given as additional treatments to each treatment group 
beginning at Week 12 
&21),'(17,$/
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4.3.
Prior/Concomitant Medication Variables 
Medications (prior or concomitant) will be recorded and will be coded to Anatomical 
Therapeutic Chemical (ATC) according to World Health Organization Drug Dictionary (WHO 
Drug Dictionary) March 2016 enhanced version provided by Bayer Health Care. 
Medications will be summarized as follows: 
x
Prior medication is defined as medications that are started before and ended before a 
patient received the first study treatment. 
x
Concomitant medication is defined as medications that are ongoing at or begin after 
the start of study treatment. 
x
New medication is defined as medication that began after the start of study treatment. 
4.4.
Efficacy Variables 
Analyses of efficacy will include the variables below.  
4.4.1.
Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in BCVA measured by the ETDRS 
letter score at week 12 through week 36.  
4.4.2.
Secondary Efficacy Variables 
The secondary efficacy variables are: 
x
Change from baseline in central subfield retinal thickness (CST) at week 12 through 
week 36 as measured by SD-OCT
x
Proportion of patients with a ≥2-step improvement in Diabetic Retinopathy Severity 
Scale (DRSS) from baseline at week 12 through week 36 
4.4.3.
Additional Efficacy Variables 
The additional efficacy variables are:  
x
Area under curve (AUC) for BCVA from baseline at week 12 through week 36* 
x
Proportion of patients who gain any letters (> 0 letter) and ≥ 5, 10, 15 ETDRS letters 
from baseline at week 12 through week 36 
x
Proportion of patients who lose ≥ 5, 10 and 15 ETDRS letters from baseline at week 
12 through week 36 
x
Proportion of patients who achieve BCVA of ≥68 letters (20/40 Snellen equivalent) at 
week 12 through week 36  
x
AUC for CST from baseline at week 12 through week 36* 
x
Proportion of patients with a ≥ 2-step worsening from baseline in the ETDRS DRSS 
at week 12 through week 36 
&21),'(17,$/
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x
Proportion of patients with a ≥ 3-step improvement from baseline in the ETDRS 
DRSS at week 12 through week 36 
x
Proportion of patients with a ≥ 3-step worsening from baseline in the ETDRS DRSS 
at week 12 through week 36 
x
Proportion of patients with no retinal and/or subretinal fluid**at week 12 through 
week 36
x
Time to no retinal and/or subretinal fluid**  
x
Proportion of patients with absence of DRIL*** at week 12 through week 36. 
*For changes in CST and BCVA, and AUC for CST and BCVA, analyses will also be performed 
using the change from week 12 to week 36. Here, AUC will be calculated as a weighted average 
based on total AUC (using the trapezoidal rule) divided by total duration in days. 
**Retinal and/or subretinal fluid is assessed using Intraretinal Fluid (IRF) Cystoid Edema and 
Subretinal Fluid (SRF). If answers are “No” to both measurements, there is no Retinal and/or 
subretinal fluid (Dry); if “Yes” to any of the two measurements, there is Retinal and/or subretinal 
fluid (Not Dry); other than the previous two cases, Retinal and/or subretinal fluid is 
undetermined. 
***Absence of DRIL is the opposite answer to the assessment of DRIL: absence of DRIL is 
“Yes” if “No” to the assessment of DRIL; absence of DRIL is “No” if “Yes” to the assessment of 
DRIL. Otherwise, DRIL is undetermined.  
4.5.
Safety Variables 
4.5.1.
Adverse Events and Serious Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered a study 
drug which may or may not have a causal relationship with the study drug.  
AEs will be collected from the time of informed consent signature and at each visit until the end 
of the study. If the patient withdraws from the study during the screening, AEs will be collected 
up until the patient withdraws. If the patient withdraws after receiving the first dose of study 
medication, AEs will be collected up until end of study or early termination, whichever is earlier, 
and will be coded using MedDRA version 20.0 with the Lowest Level Terms (LLT), the 
Preferred Term (PT), and the primary System Organ Class (SOC). 
AEs will be summarized as: 
x
Pre-treatment AE: Include adverse events that occur after the patient has signed the 
informed consent, but prior to Visit 2 (Day 1- date of the patient’s first dose of study 
drug).
x
Treatment-Emergent Adverse Event (TEAE): TEAE is defined as an AE that is 
observed or reported after first and not later than 30 days after last administration of 
study medication (REGN910-3/IAI/sham as scheduled or additional treatment) in 
study eye. Only worsening, pre-existing AEs and new AEs reported during treatment 
period (period after first treatment) will be collected in the study. 
&21),'(17,$/
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Other variables for AE description and analysis will include AE Verbatim Term, AE start date 
and end date/ongoing and corresponding study day, AE duration, relationship of AE to study 
drug, relationship of AE to study procedure, relationship to injection procedure, seriousness, 
intensity, action due to AE, treatment of AE, and outcome. 
4.5.2.
Surgeries 
All surgeries after informed consent are collected on the CRF and are coded by MedDRA. The 
following variables will be tabulated by MedDRA preferred term: 
x
Pre-treatment surgery is defined as surgery performed before the start of study 
treatment 
x
Treatment emergent surgery is defined as surgery that is started on or after the first 
study treatment.  

Ocular treatment emergent surgery for study eye and fellow eye 

Non-ocular treatment emergent surgery 
4.5.3.
Laboratory Safety Variables 
Clinical laboratory variables will include the following: 
x
Chemistry panel: Sodium, Potassium, Chloride, Carbon dioxide, Calcium, Glucose, 
Albumin, Total protein, serum, Creatinine, Blood urea nitrogen (BUN), Aspartate 
aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase, 
Lactate dehydrogenase, Total bilirubin, Total cholesterol, Triglycerides, Uric acid, 
Creatine phosphokinase 
x
Hematology panel: Hemoglobin, Hematocrit, Red blood cells (RBCs), White blood 
cells (WBCs), Red cell indices, Platelet count, Neutrophils, Lymphocytes, 
Monocytes, Basophils, Eosinophils 
x
Urinalysis: Urine Protein Creatinine Ratio (UPCR), Color, Clarity, pH, Specific 
gravity, Ketones, Protein, Glucose, Blood, Bilirubin, Leukocyte esterase, Nitrite, 
WBC, RBC, Hyaline and other casts, Bacteria, Epithelial cells, Crystals, Yeast 
x
HbA1C 
4.5.4.
Ocular Safety Measures 
Variables of analysis for ocular safety measures include: 
x
Proportion of patients with increased intraocular pressure (IOP): 

≥ 10 mmHg increase in IOP measurement from baseline to any pre-dose 
measurement 

> 21 mmHg for any pre-dose measurement 

≥ 25 mmHg for any pre-dose measurement 

≥ 35 mmHg at any time during the study
Post dose IOP measurement should be the last IOP recorded. 
&21),'(17,$/
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4.5.5.
Electrocardiogram 
A standard 12-lead ECG will be performed. The 12-Lead ECG parameters include: ventricular 
rate, the PR interval, QRS interval, RR interval, QT interval, QT interval with Bazett and 
Fridericia correction, and ECG status (normal or abnormal). 
4.5.6.
Vital Signs 
Variables of analysis for vital signs include temperature, heart rate, and blood pressure measures. 
4.5.7.
Immunogenicity 
Antibody (ADA) serum samples collected pre-dose at day 1 (visit 1 or 2), Week 20 (visit 7), and 
Week 36 (visit 11/end of study) or early termination will be analyzed for anti-REGN910 
antibodies and anti-VEGF Trap antibodies, separately. The following variables will be described: 
x
Total number of patients whose response in the ADA assay is negative at all 
timepoints analyzed 
x
Pre-existing immunoreactivity defined either as a baseline positive ADA assay 
response (pre-dose at visit 1 or 2) with all post-dose ADA assay results negative, or a 
baseline positive assay response with all post-dose ADA assay responses less than 
4-fold over baseline titer levels. 
x
Treatment-emergent positive ADA response defined as any post-dose positive ADA 
assay response when there is no baseline positive ADA assay response. 
x
Treatment-boosted positive ADA response defined as any post-dose positive ADA 
assay response that is at least a 4-fold over the baseline titer level when baseline is 
positive in the ADA assay. 
x
Titer values for positive ADA assay response (Titer value category) 

Low (titer < 1,000) 

Moderate (1,000 ≤ titer ≤ 10,000)

High (titer > 10,000) 
4.5.8.
Pharmacokinetic Variables 
Concentrations of REGN910 in serum and concentrations of free aflibercept and adjusted bound 
aflibercept in plasma will be summarized over time, and at each visit through week 36. 
&21),'(17,$/
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5.
STATISTICAL METHODS 
All safety and efficacy variables will be summarized descriptively with appropriate statistical 
methods: categorical variables by frequency tables (absolute and relative frequencies) and 
continuous variables by sample statistics (i.e. mean, standard deviation, minimum, median, 
quartiles and maximum).  Continuous variables will be described by Visit and as change from 
Baseline or Week 12, if applicable. Efficacy variables will be analyzed descriptively.  No formal 
statistical testing will be provided, however confidence intervals and nominal p-values will be 
provided. 
A summary of efficacy and safety analyses is presented in Appendix 10.2.
5.1.
Demographics, Baseline Characteristics, Medical History, and 
Prior/Concomitant Medication 
Demographic data and baseline characteristics variables, described in Section 4.1, will be 
summarized using descriptive statistics for SAF, FAS, and FAS Secondary Randomization. 
Medical history is evaluated in SAF population by frequency tables, showing number of patients 
with medical history findings by primary system organ class (SOC), and high level term (HLT) 
by MedDRA terms. 
Prior/concomitant medication will be summarized in SAF population by WHO-DD March 2016 
enhanced version ATC codes (ATC 3-digit class and ATC 5-digit subclass) for medication taken 
during the study.  Separate frequency tables will be displayed for patients with prior medications, 
new medications and concomitant medications by the time periods described in Section 4.3.
New and concomitant medications will be summarized by the period from Day 1 up to Week 36 
(End of study). 
5.2.
Patient Disposition 
Patient disposition will include:  
x
The total number of screened patients who met the inclusion criteria regarding the 
target indication, and signed the ICF (Informed consent form) 
x
The total number of randomized patients at the initial randomization who receive a 
randomization number 
x
The total number of patients at the re-randomization at Week 12 for group 2 and 3 
x
The total number or patients in each analysis set (e.g., FAS, SAF, etc.) 
x
The total number of patients who discontinued the study before Week 12 and 
Week 36 with the reasons for discontinuation 
The following listings will be provided to assess the patient disposition: 
x
A listing of patients treated but not randomized, and patients randomized but not 
treated, based on both the initial randomization and the secondary randomization at 
Week 12 
&21),'(17,$/
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x
A listing of patients who discontinued from study, along with reasons for 
discontinuation 
x
A listing of patients who received additional treatment in the study eye, including the 
total number of additional treatments and the visits at which they received additional 
treatment 
x
A listing of major protocol deviations  
5.3.
Compliance, Exposure, and Additional Treatment 
The variables for dose exposure, compliance, and additional treatment described in Section 4.2
will be summarized for the study eye in SAF and “SAF Secondary Randomization” populations, 
using descriptive statistics by the following time periods: 
x
Day 1 to Week 12  
x
Day 1 to Week 36, End of study 
5.4.
Efficacy Analyses 
Efficacy analyses of all efficacy variables at Week 12 defined in Section 4.4 will be conducted 
using the FAS population, and after Week 12 using “FAS Secondary Randomization” 
population. The analysis on the FAS at Week 12 will be performed according to the treatment 
assigned at baseline (as randomized). Week 36 analysis will be performed according to the 
treatment assigned (as randomized) at Week 12 for group 2 and 3 (high dose and IAI, 
respectively) or at baseline for group 1 (low dose). 
5.4.1.
Analysis of Efficacy Variables 
5.4.1.1.
Primary Analysis of Primary Efficacy Variable 
The primary analysis of primary efficacy variables at Week 12 is an ANCOVA model with 
baseline measure as a covariate and treatment group as a fixed factor.  The least squares mean 
and the 2-sided 95% confidence interval of the difference (each of REGN910-3 groups minus 
IAI groups) will be calculated.  For analysis after Week 12, since patients are re-randomized and 
stratified by BCVA, the analysis will use an ANCOVA model with baseline measure as a 
covariate and fixed factors including treatment group and BCVA stratification variable.  For 
group 2 and 3 (high dose and IAI, respectively), the BCVA stratification variable from IVRS for 
re-randomization will be used.  For group 1 (low dose), the BCVA stratification variable will be 
derived from BCVA measurement in EDC at Week 12 since group 1 was not re-randomized and 
BCVA stratification variable was not available in IVRS. 
For patients receiving additional treatment, their assessments will be set to missing from the next 
visit after the first additional treatment. If the assessments are missing, the last post-baseline 
efficacy variable on or prior to receiving additional treatment will be carried forward (LOCF) for 
the assessments. 
The analysis will be performed at Week 12 using FAS population and after Week 12 using “FAS 
Secondary Randomization” population. 
&21),'(17,$/
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5.4.1.2.
Sensitivity Analyses of Primary Efficacy Variable 
Several sensitivity analyses will be performed to address the impact of missing data due to
drop-outs or receiving additional treatment. All sensitivity analyses described below will be 
analyzed at Week 12 using FAS population and after Week 12 using FAS population and “FAS 
Secondary Randomization” population. 
The following sensitivity analyses are used for the primary efficacy variable: 
x
Observed case (OC) analysis 
Only patients that have the measurement available at a given time-point will be used. 
For patients receiving additional treatment, their assessments will be censored from 
the next visit after the first additional treatment. 
x
Multiple Imputation (MI) analysis 
This approach assumes that the efficacy variables are missing at random. Multiple 
imputation involves the following three steps:  
a.
Imputation – In this step, missing data will be imputed 100 times to generate 100 
completed datasets. The missing data will be imputed by a two-step procedure. 

First missing data will be imputed in order to achieve a monotone missing 
pattern using the MCMC (Markov Chain Monte Carlo) method 

Subsequently, missing data will be imputed by a regression model using the 
same covariates as the primary efficacy model  
b. Analysis – This is the general analysis step using the multiple imputed datasets as 
completed sets and will be performed for each of 100 imputed datasets. Analysis 
model will be the same as the primary efficacy analysis. 
c.
Pooling – The combination of the different parameter estimates across the 
multiple datasets based on Rubin’s rules produce a unique point estimate and 
standard error taking into account the uncertainty of the imputation process. 
x
Patients who have received additional treatment 
In these analyses the value at the given timepoint will be used regardless of whether 
the patient received additional treatment or not. Two different analyses will be 
conducted:

Ancillary LOCF (aLOCF) – Data obtained after the initiation of additional 
treatment will be included; missing data will be imputed by LOCF. The data will 
be analyzed in the same way as described for the primary analysis in 
Section 5.4.1.1.

Ancillary observed case (aOC) - All observed values will be used for analysis, 
including measurements taken after the initiation of additional treatment is given. 
Missing data will not be imputed. The data will be analyzed in the same way as 
described for the primary analysis in Section 5.4.1.1.
&21),'(17,$/
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5.4.2.
Analysis of Secondary Efficacy Variables 
5.4.2.1.
Analyses of Continuous Secondary Efficacy Variable 
Continuous secondary efficacy variable will be analyzed similarly as primary efficacy variable in 
Section 5.4.1.1.
The same LOCF approach for missing measurements used for the primary efficacy variable will 
be applied to the continuous efficacy variables. For sensitivity analyses, OC, aOC, and aLOCF 
approaches mentioned in Section 5.4.1.2 will be used for the continuous efficacy variables. 
5.4.2.2.
Analyses of Categorical Secondary Efficacy Variable 
The proportion of patients with a≥2-step improvement in DRSS will be summarized by 
frequencies and percentages.  
For Week 12 analysis, a 2-sided 95% confidence interval using normal approximation for the 
treatment difference (each of REGN910-3 groups minus the IAI group) will be calculated.  For 
analysis after Week 12, since patients are re-randomized and stratified by BCVA, the 
Cochran-Mantel-Haenszel weighted test adjusted by the same BCVA stratification factor as in 
the primary analysis (see Appendix 10.5) will be used to generate a 2-sided 95% confidence 
interval using normal approximation for the treatment difference (each of REGN910-3 groups 
minus the IAI group).  
The same LOCF approach for missing measurements used for the primary efficacy variable will
be applied to the categorical variables.  For sensitivity analyses, OC, aOC, and aLOCF 
approaches mentioned in Section 5.4.1.2 will be used.  
In order to analyze the step improvement, DRSS will be mapped to Severity Level based on 
Appendix 10.7. Note that DRSS of 90 (cannot grade) will be mapped to severity level of 90.  
Missing data in the LOCF and aLOCF approaches will be imputed by the last non-missing 
(including 90) post-baseline severity level.  However, the percentage will be calculated based on 
the evaluable patients (excluding 90). 
5.4.3.
Analysis of Additional Efficacy Variables 
5.4.3.1.
Analyses of Continuous Additional Efficacy Variables 
Continuous additional efficacy variables will be analyzed similarly as primary efficacy variable 
in Section 5.4.1.1.
The same LOCF approach for missing measurements used for the primary efficacy variable will 
be applied to the continuous efficacy variables. For sensitivity analyses, OC, aOC, and aLOCF 
approaches mentioned in Section 5.4.1.2 will be used for the continuous efficacy variables. 
5.4.3.2.
Analyses of Categorical Additional Efficacy Variables 
Proportion of patients who gain ≥ 15 ETDRS letters and proportion of patients with no retinal 
and/or subretinal fluid will be analyzed similarly as categorical secondary efficacy variable in 
Section 5.4.2.2. Other categorical additional efficacy variables will be summarized descriptively. 
&21),'(17,$/
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The same LOCF approach for missing measurements used for the primary efficacy variable will 
be applied to the categorical efficacy variables. For sensitivity analyses, OC, aOC, and aLOCF 
approaches mentioned in Section 5.4.1.2 will be used. 
5.4.3.3.
Analyses of Time-to event Additional Efficacy Variables 
Event is defined as the first time patient has no retinal and/or subretinal fluid (“No” for both 
measurements of IRF and SRF) without taking additional treatment previously.  Otherwise, 
patient is censored at the date of receiving additional treatment or the date of last available OCT 
measurements, whichever is earlier.  The analysis will be based on observed case only using the 
Kaplan-Meier method. 
5.4.4.
Additional Analysis due to IVRS Dosing Error  
A programming error that affected the dosing schedule was identified in the IRT system.  Due to 
this IVRS system error, a majority of patients in group 1 (REGN910-3 3 mg:2 mg -low dose) 
were given 2Q4 dosing instead of the planned 2Q8 dosing after week 12. Some patients were 
given one extra dose at Week 20; some were given two extra doses at both Week 20 and 
Week 28.  About half of patients in group 2b (REGN910-3 6 mg:2 mg -high dose 2Q12) were 
given an injection at Week 28 (8 weeks after the previous injection). Some patients had 1 dosing 
error at week 28 (active instead of Sham at week 28 and Active at week 32); some had two 
dosing errors (active at week 28 and Sham at week 32). The following analyses will be 
implemented to address the impact of the dosing error for primary and secondary efficacy 
variables. 
x
Subgroup analysis: At Week 36, a subgroup analysis for patients with no dosing error 
will be performed in addition to original analysis at Week 36. However, this subgroup 
analysis will exclude group 1a since the majority of patients in group 1a had a dosing 
error. 
x
Week 20 analysis: Primary and secondary efficacy variables will be analyzed at 
Week 20 prior to the introduction of the dosing error impacting group 1a (low dose). 
Week 20 analysis will only evaluate Q8 groups as Q12 groups are not synchronized 
with respect to time since last active dose. 
x
Week 28 analysis: Primary and secondary efficacy variables will be analyzed at 
Week 28 prior to introduction of dosing error impacting group 2b (high dose Q12). 
Week 28 analysis will only evaluate Q12 groups as Q8 groups are not synchronized 
with respect to time since last active dose. 
5.5.
Analysis of Safety Data 
Safety data, such as AE, surgeries, and IOP through Week 36 will be summarized in the SAF and 
SAF Secondary Randomization populations using descriptive statistics.  The analysis on the SAF 
will be performed according to the treatment assigned at baseline (as randomized).  Week 36 
analysis on the SAF Secondary Randomization population will be performed according to the 
treatment assigned (as randomized) at Week 12 for group 2 and 3 (high dose and IAI, 
respectively) or at baseline for group 1 (low dose).  Other safety data, such as lab, vital signs and 
ECG will be summarized in the SAF Secondary Randomization population descriptively 
&21),'(17,$/
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according to the treatment assigned (as randomized) at Week 12 for group 2 and 3 (high dose 
and IAI, respectively) or at baseline for group 1 (low dose).  For patients who are not 
re-randomized, their lab, vital signs and ECG data will be listed according to the treatment 
assigned at baseline. 
5.5.1.
Adverse Events 
AE summaries will be constructed displaying frequencies and proportions of patients reporting 
AEs within each SOC in decreasing order of total frequency according to the numbers of patients 
reporting the SOC and the AE within the SOC (not number of reports).  
AEs will be classified as Pre-treatment AEs and TEAEs, and will further be summarized by the 
following categories: 
x
Ocular AEs in the study eye 
x
Ocular AEs in the fellow eye 
x
Non-ocular AEs 
Serious Adverse Events (SAEs), drug-related AEs, drug-related SAEs, and TEAEs leading to 
discontinuation will be summarized in the same way as described for TEAEs. 
TEAEs in the study eye related to the injection procedure and those related to the study 
medication will be summarized separately. 
The summaries of the number of patients with TEAEs through Week 36 will be given by 
treatment group: 
x
The analysis on the SAF will be performed according to the treatment assigned at 
baseline (as randomized).  
x
The analysis on the SAF Secondary Randomization population will be performed 
according to the treatment assigned (as randomized) at Week 12 for group 2 and 3 
(high dose and IAI, respectively) or at baseline for group 1 (low dose). 
An overall summary of the AE profile for REGN910-3/IAI through Week 36 will be provided. 
A listing will be constructed that includes the patient identification, the treatment group, category 
of AE (ocular study/fellow eye, non-ocular), AE, MedDRA term, seriousness, severity, causality, 
elapsed time to onset, duration, and outcome.  
Adjudicated APTC events, intraocular inflammation and hypertension will be tabulated and 
listed. 
The detailed definitions of the preferred terms for intraocular inflammation and hypertension are 
presented in Appendix 10.3.
5.5.2.
Surgeries 
An overall summary of number of patients undergoing surgery as described in Section 4.5.2
through Week 36 will be given by treatment group in the SAF and SAF Secondary 
Randomization populations. 
&21),'(17,$/
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5.5.3.
Clinical Laboratory 
Baseline clinical laboratory analytic values and change from baseline to each scheduled 
assessment visit in clinical laboratory analytic values will be summarized with descriptive 
statistics for Week 36 analyses in the SAF Secondary Randomization population.  Shift tables 
will also be provided for abnormalities. For patients who are not re-randomized, their data will 
be listed according to the treatment assigned at baseline. 
Predefined lab abnormalities will be identified for selected clinical laboratory values according 
to the specified ranges (see Appendix 10.4). The frequency and percentage of patients with at 
least one predefined lab abnormalities during the treatment period will be displayed by treatment 
group for each analyte. 
Lab values out of normal range will be flagged in lab value listings. 
5.5.4.
Vital Signs 
Vital signs will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics for Week 36 analyses in the SAF Secondary 
Randomization population. For patients who are not re-randomized, their data will be listed 
according to the treatment assigned at baseline. 
5.5.5.
Ocular Safety Measures 
Frequency tables will be provided on the variables listed in Section 4.5.4 by treatment groups 
and visits for Week 36 analyses in the SAF and SAF Secondary Randomization population.  For 
patients who are not re-randomized, their data will be listed according to the treatment assigned 
at baseline. 
Baseline IOP and change from Baseline in IOP to each scheduled assessment visit will be 
summarized with descriptive statistics for study eye and fellow eye. 
5.5.6.
Electrocardiogram 
All ECG variables as described in Section 4.5.5 will be analyzed by appropriate descriptive 
methods for Week 36 analyses in the SAF Secondary Randomization population.  For patients 
who are not re-randomized, their data will be listed according to the treatment assigned at 
baseline.  Change from baseline or frequency tables, and/or cross tabulation of baseline vs. 
post-baseline status for categorical variables (overall interpretation of ECG normal/abnormal, 
and clinical relevant abnormalities no/yes) by visit and treatment group will be included. 
5.5.7.
Analysis of Drug Concentration Data 
The concentrations of REGN910 in serum and concentrations of free aflibercept and adjusted 
bound aflibercept in plasma will be analyzed to include descriptive statistics at each sampling 
time. 
5.5.8.
Immunogenicity 
The following summaries will be performed based on ADA analysis set for Week 36 analysis:  
x
Listing of ADA results (negative or titer value for positive ADA) by patient, visit and 
cohort 
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x
Incidence of pre-existing immunoreactivity, treatment-emergent, and 
treatment-boosted ADA assay responses assessed as absolute occurrence (N) and 
percent of patients (%), grouped by cohort 
x
Potential impact of treatment-emergent or treatment-boosted ADA assay response on 
safety or efficacy may be evaluated
6.
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1.
Definition of Baseline 
Unless otherwise specified, the Baseline assessment for all measurements will be the last 
available valid measurement taken prior to the first administration of investigational product.  
For efficacy analysis after Week 12, the Baseline is defined as the measurement at Week 12. 
6.2.
Handling of Missing Data 
When appropriate, the following rules will be implemented so as not to exclude patients from 
statistical analyses due to missing or incomplete data: 
x
Efficacy Variables 
Rules for handling missing data for primary, secondary, and additional efficacy variables are 
described in the efficacy analysis section (see Section 5.4).
x
AE variables 
For some AEs it is important to determine whether the AE started before or after the first 
REGN910-3/IAI injection. If the AE start date is partially missing, it will be imputed by the 
latest possible date (considering other available data, e.g., stop date) to be conservative. 
x
Prior/concomitant medication 
For the tabulation of prior and concomitant medication, partially missing start dates of the 
medication will be imputed by the earliest possible time point, partially missing stop dates will 
be imputed by the latest possible time point. 
x
Medication coding 
Medications whose ATC level 4 (5-digit class) cannot be coded will be summarized by setting 
ATC4 (5-digit class)=ATC2 (3-digit class) in the table programs. However, these uncoded ATC 
level 4 records still need to be confirmed with study Data Manager and study Medical Director. 
6.3.
Unscheduled Assessments 
Assessments taken outside of protocol allowable windows will be displayed according to the 
case report form (CRF) assessment recorded by the investigator.  
Unscheduled and extra assessments (laboratory data or vital signs associated with non-protocol 
clinical visits, or obtained in the course of investigating or managing AEs) will be included in 
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listings but not summaries, with the exception of IOP measurements.  If more than 1 laboratory 
value is available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
Early termination visit (ET): For efficacy assessments, the ET visit will be re-slotted to the next 
visit after the last scheduled visit if ET visit was performed 4 weeks (+/- 1 week) after the last 
scheduled visit. ET visits outside the window will be treated as unscheduled assessments, that is, 
will not be used for analyses and will only be shown in the patient listings. 
7.
INTERIM ANALYSIS  
No interim analysis is planned in this study. 
8.
SOFTWARE 
All analyses will be done using SAS Version 9.2 or later. 
9.
REFERENCES 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
Moser BK, Stevens GR, Watts CL.  The two-sample t-test versus Satterthwaite’s approximate 
f test.  Communications in Statistics – Theory and Methods 1989;18(11);3:963-3975. 
&21),'(17,$/
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6. 
Indirect ophthalmoscopy should be performed at all study visits (bilateral).  On days when study drug is administered, it should be performed pre-dose 
(bilateral) and immediately after administration of study drug (study eye only). 
7. 
Vital signs (body temperature, blood pressure, and heart rate) should be measured after the patient has been sitting for 5 minutes. 
8. 
If a patient withdraws from the study, ongoing AEs should be followed to the end of study visit or until the patient withdraws consent. 
9. 
All samples collected for laboratory assessments should be obtained prior to administration of study drug. 
10. For women of childbearing potential, a negative serum pregnancy test at screening is required for eligibility.  All women of childbearing potential will have 
a urine pregnancy test at each treatment visit starting at visit 2 (day 1).  A negative urine pregnancy test is required before treatment is administered. 
11. PK samples (serum for REGN910 and plasma for aflibercept) should be drawn pre-dose on all visits through week 32.  All ADA serum samples should be 
collected prior to administration of study drug.  
12. The genomic sub-study ICF should be presented to patients at the screening visit and may be signed at any subsequent visit at which the patient chooses to 
participate after screening.  The genomic DNA sample should only be collected on day1/baseline (pre-dose) or at any study visit from patients who have 
signed the sub-study ICF. 
&21),'(17,$/
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10.2.
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint
Analysis Populations
Statistical Analysis
Main
Analysis
Sensitivity Analysis
Primary efficacy endpoint
The change from baseline in BCVA measured by the ETDRS letter 
score at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Secondary efficacy endpoints
Change from baseline in CST at weeks 12 through 36 as measured by 
SD-OCT
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Proportion of patients with a ≥2-step improvement in DRSS from 
baseline at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Additional efficacy endpoints
AUC for BCVA from baseline at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
OC
aOC
Proportion of patients who gain any letters (> 0 letter) and ≥ 5, 10, 15 
letters from baseline at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Proportion of patients who lose ≥ 5, 10 and 15 ETDRS letters from 
baseline at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Proportion of patients who achieve BCVA of ≥68 letters (20/40 
Snellen equivalent) at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
AUC for CST from Baseline at weeks 12 through 36
FAS, FAS secondary
randomization set
Descriptive Statistics
OC
aOC
Proportion of patients with a ≥ 2-step worsening from baseline in the 
ETDRS DRSS at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Proportion of patients with a ≥ 3-step improvement from baseline in 
the ETDRS DRSS at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
&21),'(17,$/
995,0$SSURYHG2FW*07


Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 31 of 40
Proportion of patients with a ≥ 3-step worsening from baseline in the 
ETDRS DRSS at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
LOCF
OC, aOC, and aLOCF
Proportion of patients with no retinal and/or subretinal fluid at weeks 
12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
OC
aOC
Time to no retinal and/or subretinal fluid at weeks 12 through 36
FAS, FAS secondary 
randomization set
Descriptive Statistics
OC
Proportion of patients with absence of DRIL at weeks 12 through 36.
FAS, FAS secondary 
randomization set 
Descriptive Statistics
Descriptive Statistics
OC
aOC
Safety Analyses: 
Endpoint
Analysis Populations
Statistical Method
AEs and SAEs
SAF,
SAF Secondary Randomization
Descriptive Statistics
Surgeries
SAF,
SAF Secondary Randomization
Descriptive Statistics 
Laboratory 
SAF Secondary Randomization
Descriptive Statistics; Shift tables
ECG
SAF Secondary Randomization
Descriptive Statistics
Vital Signs
SAF Secondary Randomization
Descriptive Statistics
Ocular Safety Measures
SAF,
SAF Secondary Randomization
Descriptive Statistics
&21),'(17,$/
995,0$SSURYHG2FW*07


Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 32 of 40
10.3.
Detailed Definition of Selected Subgroups 
The preferred terms for the definitions of hypertension and intraocular inflammation below are 
based on MedDRA version 20.0. 
10.3.1.
Hypertension 
MSSO SMQ
MSS SMQ CODE
Preferred term
Hypertension
20000147
Accelerated hypertension
Hypertension
20000147
Aldosterone urine abnormal
Hypertension
20000147
Aldosterone urine increased
Hypertension
20000147
Angiotensin I increased
Hypertension
20000147
Angiotensin II increased
Hypertension
20000147
Angiotensin converting enzyme increased
Hypertension
20000147
Blood aldosterone abnormal
Hypertension
20000147
Blood aldosterone increased
Hypertension
20000147
Blood catecholamines abnormal
Hypertension
20000147
Blood catecholamines increased
Hypertension
20000147
Blood pressure abnormal
Hypertension
20000147
Blood pressure ambulatory abnormal
Hypertension
20000147
Blood pressure ambulatory increased
Hypertension
20000147
Blood pressure diastolic abnormal
Hypertension
20000147
Blood pressure diastolic increased
Hypertension
20000147
Blood pressure fluctuation
Hypertension
20000147
Blood pressure inadequately controlled
Hypertension
20000147
Blood pressure increased
Hypertension
20000147
Blood pressure management
Hypertension
20000147
Blood pressure orthostatic abnormal
Hypertension
20000147
Blood pressure orthostatic increased
Hypertension
20000147
Blood pressure systolic abnormal
Hypertension
20000147
Blood pressure systolic increased
Hypertension
20000147
Catecholamines urine abnormal
Hypertension
20000147
Catecholamines urine increased
Hypertension
20000147
Diastolic hypertension
Hypertension
20000147
Diuretic therapy
Hypertension
20000147
Eclampsia
Hypertension
20000147
Ectopic aldosterone secretion
Hypertension
20000147
Ectopic renin secretion
&21),'(17,$/
995,0$SSURYHG2FW*07


Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 33 of 40
Hypertension
20000147
Endocrine hypertension
Hypertension
20000147
Epinephrine abnormal
Hypertension
20000147
Epinephrine increased
Hypertension
20000147
Essential hypertension
Hypertension
20000147
Gestational hypertension
Hypertension
20000147
HELLP syndrome
Hypertension
20000147
Hyperaldosteronism
Hypertension
20000147
Hypertension
Hypertension
20000147
Hypertension neonatal
Hypertension
20000147
Hypertensive angiopathy
Hypertension
20000147
Hypertensive cardiomegaly
Hypertension
20000147
Hypertensive cardiomyopathy
Hypertension
20000147
Hypertensive cerebrovascular disease
Hypertension
20000147
Hypertensive crisis
Hypertension
20000147
Hypertensive emergency
Hypertension
20000147
Hypertensive encephalopathy
Hypertension
20000147
Hypertensive heart disease
Hypertension
20000147
Hypertensive nephropathy
Hypertension
20000147
Labile blood pressure
Hypertension
20000147
Labile hypertension
Hypertension
20000147
Malignant hypertension
Hypertension
20000147
Malignant hypertensive heart disease
Hypertension
20000147
Malignant renal hypertension
Hypertension
20000147
Maternal hypertension affecting foetus
Hypertension
20000147
Mean arterial pressure increased
Hypertension
20000147
Metabolic syndrome
Hypertension
20000147
Metanephrine urine abnormal
Hypertension
20000147
Metanephrine urine increased
Hypertension
20000147
Neurogenic hypertension
Hypertension
20000147
Non-dipping
Hypertension
20000147
Norepinephrine abnormal
Hypertension
20000147
Norepinephrine increased
Hypertension
20000147
Normetanephrine urine increased
Hypertension
20000147
Orthostatic hypertension
Hypertension
20000147
Page kidney
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 34 of 40
Hypertension
20000147
Pre-eclampsia
Hypertension
20000147
Prehypertension
Hypertension
20000147
Procedural hypertension
Hypertension
20000147
Pseudoaldosteronism
Hypertension
20000147
Renal hypertension
Hypertension
20000147
Renal sympathetic nerve ablation
Hypertension
20000147
Renin abnormal
Hypertension
20000147
Renin increased
Hypertension
20000147
Renin-angiotensin system inhibition
Hypertension
20000147
Renovascular hypertension
Hypertension
20000147
Retinopathy hypertensive
Hypertension
20000147
Secondary aldosteronism
Hypertension
20000147
Secondary hypertension
Hypertension
20000147
Systolic hypertension
Hypertension
20000147
Tyramine reaction
Hypertension
20000147
Withdrawal hypertension
10.3.2.
Intraocular Inflammation 
Preferred term
Anterior chamber cell
Anterior chamber fibrin
Anterior chamber flare
Anterior chamber inflammation
Aqueous fibrin
Autoimmune uveitis
Chorioretinitis
Choroiditis
Cyclitis
Endophthalmitis
Eye infection intraocular
Eye inflammation
Hypopyon
Infective iritis
Infective uveitis
Infectious iridocyclitis
Iridocyclitis
&21),'(17,$/
995,0$SSURYHG2FW*07


Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 35 of 40
Iritis
Non-infectious endophthalmitis
Non-infective chorioretinitis
Pseudoendophthalmitis
Uveitis
Vitreal cells
Vitreous fibrin
Vitritis
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 36 of 40
10.4.
Criteria for Predefined Lab Abnormalities 
Parameter
Potentially clinically significant value (PCSV)
Clinical Chemistry
ALT
By distribution analysis:
> 3 ULN
AST
By distribution analysis:
> 3 ULN
Alkaline Phosphatase
> 1.5 ULN
Total Bilirubin
> 1.5 ULN
ALT and Total Bilirubin
ALT > 3 ULN and Total Bilirubin > 2 ULN
CPK
> 3 ULN
Creatinine
t 150 μmol/L (Adults)
t 30% from baseline
Uric Acid
Hyperuricemia: >408 μmol/L
Hypouricemia: <120 μmol/L
Blood Urea Nitrogen
t 17 mmol/L
Chloride
< 80 mmol/L
> 115 mmol/L
Sodium
d 129 mmol/L
t 160 mmol/L
Potassium
< 3 mmol/L
t 5.5 mmol/L
Total Cholesterol
t 7.74 mmol/L (3 g/L)
Triglycerides
t 4.6 mmol/L (4 g/L)
Lipasemia
t 3 ULN
Glucose
- Hypoglycaemia
- Hyperglycaemia
d 3.9 mmol/L and < LLN
t 11.1 mmol/L (unfasted), t 7 mmol/L (fasted)
HbA1c
> 8 %
Albumin
d 25 g/L
Hematology
WBC
< 3.0 GIGA/L (non-Black), < 2.0 GIGA/L (Black), t 16.0 GIGA/L
Lymphocytes
> 4.0 GIGA/L
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 37 of 40
Parameter
Potentially clinically significant value (PCSV)
Neutrophils
< 1.5 GIGA/L (non-Black)
< 1.0 GIGA/L (Black)
Monocytes
> 0.7 GIGA/L
Basophils
> 0.1 GIGA/L
Eosinophils
> 0.5 GIGA/L or
> ULN if ULN t 0.5 GIGA /L
Hemoglobin
Males:
d115 g/L (d 7.14 mmol/L), t 185 g/L (11.48 mmol/L)
Females: d 95 g/L (5.9 mmol/L), t 165 g/L (10.24 mmol/L)
Decrease from Baseline t 20 g/L (1.24 mmol/L)
Hematocrit
Males:
d 0.37 v/v, t 0.55 v/v
Females: d 0.32 v/v, t 0.5 v/v
RBC
t 6 TERA/L
Platelets
< 100 GIGA/L
t 700 GIGA/L
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 38 of 40
10.5.
Calculation of Confidence Intervals using Mantel-Haenszel 
Weighting Scheme 
The confidence intervals using the Mantel-Haenszel weighting scheme will be calculated 
according to the formulas given by Koch (1990, p. 415), i.e. to compute confidence intervals for 
the difference in two binomial proportions obtained from a multicenter trial, we calculate a 
weighted difference and its associated variance using Mantel-Haenszel weighting scheme.  
For a multicenter study with h 2x2 tables, the weighted difference is: 
d = (6 wh(phe - phs))/(6 wh) 
where 
wh = nhenhs/(nhe+nhs) 
and 
phe = success rate for experimental treatment in stratum h  
phs = success rate for standard treatment in stratum h 
nhe = number of patients under experimental treatment in stratum h 
nhs = number of patients under standard treatment in stratum h 
The variance of the weighted difference is 
var(d) =(6 wh2(phs(1-phs)/(nhs -1)+ phe(1-phe)/(nhe -1)))/(6 wh)2 
A large sample approximation is used to compute the confidence interval: 
 
 
CI = d ± zD SQRT(var(d))
Where zD is the α quantile of the standard normal distribution and SQRT is the square root 
function. 
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 39 of 40
10.6.
Detailed Definition of Specific Baseline Assessments 
10.6.1.
Prior intravitreal anti-VEGF 
Prior intravitreal anti-VEGF is defined as below medications that have been taken within 
12 weeks of screening. 
Drug Generic Name
Drug Trade Name
Aflibercept (ophthalmic solution); "IAI"
Eylea
Bevacizumab
Avastin
Pegaptanib Octasodium
Macugen
Ranibizumab
Lucentis
10.6.2.
Prior intravitreal steroids 
Prior intravitreal steroids are defined as below medications that have been taken within 4 months 
of screening. 
Drug Generic Name
Drug Trade Name
Dexamethasone intravitreal implant
Ozurdex
Fluocinolone acetonide intravitreal implant
Iluvien
Intravitreal triamcinolone acetenonide
Kenalog
Intravitreal dexamethasone
Triamcinolone acetonide injectable suspension OR 
Triamconolone intravitreal injection
TRIESENCE OR Trivaris
10.6.3.
Prior focal or grid laser 
Prior focal or grid laser is defined as below preferred terms in medical history. 
Medical History Preferred Term
Retinal laser coagulation
Laser therapy
Eye laser surgery
Eye laser scar
&21),'(17,$/
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Regeneron Pharmaceuticals, Inc. 
R910-3-DME-1518 
Statistical Analysis Plan 
October 12, 2017
Page 40 of 40
10.7.
Steps for EDTRS Diabetic Retinopathy Severity Scale 
Severity Level (used to determine 
step change in DRSS)
Combined DR severity levels
Combined DR severity levels 
(as text)
1
10 and 12
DR absent
2
14, 15, 20
DR questionable, microaneurysms 
only
3
35
Mild NPDR
4
43
Moderate NPDR
5
47
Moderately severe NPDR
6
53
Severe NPDR
7
60, 61
Mild PDR
8
65
Moderate PDR
9
71
High-risk PDR
10
75
High-risk PDR
90
90
Cannot grade
&21),'(17,$/
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