RUBY: Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema

• Sponsor: Regeneron Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02712008
• Collaborator: Bayer (Industry)
• Enrollment: 302
• Locations: 51
• Arms: 8
• Duration (Months): 16.3
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: REGN910-3; Drug: Intravitreal Aflibercept Injection (IAI)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Study Start Date: Mar 2, 2016
• Actual Primary Completion Date: Jul 10, 2017
• Actual Study Completion Date: Jul 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: REGN910-3 (3 mg: 2 mg) 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.	Drug: REGN910-3; Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept)
Experimental: REGN910-3 (6 mg:2 mg) 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.	Drug: REGN910-3; Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept)
Active Comparator: Aflibercept 2 mg 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.	Drug: Intravitreal Aflibercept Injection (IAI); Other Names: EYLEA® (aflibercept) Injection BAY86-5321
Experimental: REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q8 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.	Drug: REGN910-3; Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept)
Experimental: REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 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.	Drug: REGN910-3; Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept)
Experimental: Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8 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.	Drug: Intravitreal Aflibercept Injection (IAI); Other Names: EYLEA® (aflibercept) Injection BAY86-5321
Experimental: Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12 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.	Drug: Intravitreal Aflibercept Injection (IAI); Other Names: EYLEA® (aflibercept) Injection BAY86-5321
Experimental: Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8 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.	Drug: REGN910-3; Co-formulation for intravitreal (IVT) injection consisting of REGN910 (nesvacumab) and REGN3 (aflibercept); Drug: Intravitreal Aflibercept Injection (IAI); Other Names: EYLEA® (aflibercept) Injection BAY86-5321

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 12 [Baseline, Week 12]

   Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Best Corrected Visual Acuity (BCVA) score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 12.

2. Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 36 [Baseline, Week 36]

   Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 36.

Secondary Outcome Measures

1. Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 12 [Baseline, Week 12]

   Central Sub-field Retinal Thickness (CST) was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12.

2. Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 36 [Baseline, Week 36]

   CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 36.

3. Percentage of Participants With a ≥ 2-step Improvement at Week 12 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline [Baseline, Week 12]

   The Diabetic Retinopathy Disease Severity Scale (DRSS) was used to describe overall retinopathy severity. It measured the 5 levels of diabetic retinopathy ranging from absence of retinopathy to severe retinopathy (none, mild, moderate, severe, and proliferative).

4. Percentage of Participants With a ≥ 2-step Improvement at Week 36 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline [Baseline, Week 36]

   The Diabetic Retinopathy Disease Severity Scale (DRSS) was used to describe overall retinopathy severity. It measured the 5 levels of diabetic retinopathy ranging from absence of retinopathy to severe retinopathy (none, mild, moderate, severe, and proliferative).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Men or women ≥18 years of age with type 1 or type 2 diabetes mellitus who have clinically significant DME with central involvement in the study eye

2. BCVA ETDRS letter score of 73 to 24 (Snellen equivalent of 20/40 to 20/320) in the study eye

3. Willing and able to comply with clinic visits and study-related procedures

4. Provide signed informed consent

Key Exclusion Criteria:

1. Evidence of macular edema due to any cause other than diabetes mellitus in either eye

2. IVT anti-VEGF in the study eye within 12 weeks of the screening visit

3. Panretinal laser photocoagulation or macular laser photocoagulation in the study eye within 3 months of screening

Note: Other inclusion/ exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mesa	Arizona	United States
2		Tucson	Arizona	United States
3		Arcadia	California	United States
4		Beverly Hills	California	United States
5		Mountain View	California	United States
6		Oceanside	California	United States
7		Palm Desert	California	United States
8		Colorado Springs	Colorado	United States
9		New London	Connecticut	United States
10		Lakeland	Florida	United States
11		Tampa	Florida	United States
12		Winter Haven	Florida	United States
13		Augusta	Georgia	United States
14		Decatur	Georgia	United States
15		'Aiea	Hawaii	United States
16		Chicago	Illinois	United States
17		New Albany	Indiana	United States
18		Shawnee Mission	Kansas	United States
19		Lexington	Kentucky	United States
20		Portland	Maine	United States
21		Baltimore	Maryland	United States
22		Rockville	Maryland	United States
23		Boston	Massachusetts	United States
24		Grand Rapids	Michigan	United States
25		Jackson	Michigan	United States
26		Minneapolis	Minnesota	United States
27		Florissant	Missouri	United States
28		Las Vegas	Nevada	United States
29		Bloomfield	New Jersey	United States
30		Edison	New Jersey	United States
31		Teaneck	New Jersey	United States
32		Albany	New York	United States
33		Rochester	New York	United States
34		Asheville	North Carolina	United States
35		Charlotte	North Carolina	United States
36		Kingston	Pennsylvania	United States
37		Florence	South Carolina	United States
38		West Columbia	South Carolina	United States
39		Rapid City	South Dakota	United States
40		Germantown	Tennessee	United States
41		Nashville	Tennessee	United States
42		Abilene	Texas	United States
43		Austin	Texas	United States
44		Dallas	Texas	United States
45		Fort Worth	Texas	United States
46		Harlingen	Texas	United States
47		Houston	Texas	United States
48		San Antonio	Texas	United States
49		The Woodlands	Texas	United States
50		Willow Park	Texas	United States
51		Bellevue	Washington	United States

Sponsors and Collaborators

• Regeneron Pharmaceuticals
• Bayer

Investigators

• Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 31, 2017
• Statistical Analysis Plan - Oct 12, 2017

More Information

Publications

None provided.

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02712008
• Other Study ID Numbers: R910-3-DME-1518
• First Posted: Mar 17, 2016
• Last Update Posted: Oct 3, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Macular Edema; Edema; Aflibercept

Study Results

Participant Flow

Recruitment Details	The study was conducted at 70 sites in US. A total of 438 participants were screened in the study.
Pre-assignment Detail	Out of 438 participants, 302 were randomized & treated in study. Participants were randomized in 1:2:3 to receive REGN910-3 3:2mg, REGN910-3 6:2mg & 2mg intravitreal aflibercept injection followed by re-randomization at week 12 in REGN910-3 6:2mg & IAI 2mg arm. Not all participants who completed Week 12 were re-randomized & continued to Week 36.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg)	Aflibercept 2 mg	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q8	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
Arm/Group Description	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.	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.	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.	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.	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.	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 16 and Q8 through week 32.	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.	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.
Period Title: Baseline (Day 1) up to Week 12
STARTED	50	100	152	0	0	0	0	0
COMPLETED	46	97	148	0	0	0	0	0
NOT COMPLETED	4	3	4	0	0	0	0	0
Period Title: Baseline (Day 1) up to Week 12
STARTED	45	0	0	44	52	46	48	49
COMPLETED	44	0	0	42	50	46	43	45
NOT COMPLETED	1	0	0	2	2	0	5	4

Baseline Characteristics

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg)	Aflibercept 2 mg	Total
Arm/Group Description	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	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 or Week 20 and Q8 or Q12 through week 32.	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 or REGN910-3 (6 mg:2 mg) at week 16 or 20 and Q8 through week 32.	Total of all reporting groups
Overall Participants	50	100	152	302
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (9.12)	62.5 (10.36)	59.5 (10.20)	61.0 (10.16)
Sex: Female, Male (Count of Participants)
Female	21 42%	49 49%	68 44.7%	138 45.7%
Male	29 58%	51 51%	84 55.3%	164 54.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 12%	21 21%	26 17.1%	53 17.5%
Not Hispanic or Latino	44 88%	78 78%	125 82.2%	247 81.8%
Unknown or Not Reported	0 0%	1 1%	1 0.7%	2 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2%	0 0%	3 2%	4 1.3%
Asian	1 2%	2 2%	4 2.6%	7 2.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 1%	0 0%	1 0.3%
Black or African American	11 22%	8 8%	19 12.5%	38 12.6%
White	37 74%	87 87%	121 79.6%	245 81.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 2%	5 3.3%	7 2.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 12
Description	Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Best Corrected Visual Acuity (BCVA) score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 12.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received any study drug, had baseline measurement of BCVA & at least 1 post-baseline assessment of BCVA. Last observation carried forward (LOCF) method was used to impute missing data. Here "Overall Number of Participants Analyzed" = Participants who were evaluable for this outcome measure.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg)	Aflibercept 2 mg
Arm/Group Description	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	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 or Week 20 and Q8 or Q12 through week 32.	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 or REGN910-3 (6 mg:2 mg) at week 16 or 20 and Q8 through week 32.
Measure Participants	47	99	150
Mean (Standard Deviation) [Letters correctly read]	6.8 (7.30)	8.5 (6.89)	8.8 (9.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	Analysis was performed using analysis of covariance (ANCOVA) model with baseline measurement as a covariate and treatment group as fixed factors.
Statistical Test of Hypothesis	p-Value	0.1368
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-2.09
	Confidence Interval	(2-Sided) 95%; - 4.84 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using analysis of covariance (ANCOVA) model with baseline measurement as a covariate and treatment group as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9716
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; - 2.10 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 36
Description	Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 36.
Time Frame	Baseline, Week 36

Outcome Measure Data

Analysis Population Description

FAS secondary randomization set = all participants in full analysis set (FAS) who had completed study through week 12, received any study drug after secondary randomization or after Week 12, had BCVA assessment at Week 12 & had at least 1 post-Week 16 BCVA assessment. Overall Number of Participants Analyzed=Participants evaluable for this endpoint.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q8	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
Arm/Group Description	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	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.	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.	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 16 and Q8 through week 32.	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.	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.
Measure Participants	45	44	52	46	48	49
Mean (Standard Deviation) [Letters correctly read]	9.8 (9.92)	10.3 (8.20)	8.5 (7.74)	8.7 (10.65)	10.0 (10.37)	11.9 (12.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1665
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 95%; -0.90 to 5.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2223
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	1.90
	Confidence Interval	(2-Sided) 95%; -1.16 to 4.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7943
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; -2.54 to 3.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6655
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; -2.35 to 3.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1278
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	2.33
	Confidence Interval	(2-Sided) 95%; -0.67 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3159
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-1.51
	Confidence Interval	(2-Sided) -1.51%; -4.47 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8537
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -3.18 to 2.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 12
Description	Central Sub-field Retinal Thickness (CST) was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received any study drug, had baseline measurement of BCVA & at least 1 post-baseline assessment of BCVA. Last observation carried forward (LOCF) method was used to impute missing data. Here "Overall Number of Participants Analyzed" = Participants who were evaluable for this outcome measure.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg)	Aflibercept 2 mg
Arm/Group Description	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	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 or Week 20 and Q8 or Q12 through week 32.	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 or REGN910-3 (6 mg:2 mg) at week 16 or 20 and Q8 through week 32.
Measure Participants	46	99	150
Mean (Standard Deviation) [Microns]	-169.4 (155.86)	-184.0 (143.69)	-174.6 (160.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using analysis of covariance (ANCOVA) model with baseline measurement as a covariate and treatment group as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1105
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-24.43
	Confidence Interval	(2-Sided) 95%; -54.46 to 5.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using analysis of covariance (ANCOVA) model with baseline measurement as a covariate and treatment group as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0183
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-27.79
	Confidence Interval	(2-Sided) 95%; - 50.83 to - 4.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 36
Description	CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 36.
Time Frame	Baseline, Week 36

Outcome Measure Data

Analysis Population Description

FAS secondary randomization set was used. Here "Overall Number of Participants Analyzed"= Participants who were evaluable for this endpoint.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q8	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
Arm/Group Description	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	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.	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.	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 16 and Q8 through week 32.	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.	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.
Measure Participants	44	44	52	46	48	49
Mean (Standard Deviation) [Microns]	-210.4 (164.06)	-223.4 (145.35)	-193.7 (158.29)	-161.9 (125.99)	-210.6 (202.15)	-203.7 (163.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0040
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-55.91
	Confidence Interval	(2-Sided) 95%; - 93.81 to - 18.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0365
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-40.51
	Confidence Interval	(2-Sided) 95%; -78.46 to -2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0454
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-37.15
	Confidence Interval	(2-Sided) 95%; -73.53 to -0.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9266
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; -35.54 to 39.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4116
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-15.49
	Confidence Interval	(2-Sided) 95%; -52.58 to 21.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8574
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	3.36
	Confidence Interval	(2-Sided) 95%; -33.42 to 40.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Analysis was performed using ANCOVA model with baseline measurement as a covariate, and treatment group and BCVA stratification variable as fixed factors.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0351
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	-38.90
	Confidence Interval	(2-Sided) 95%; -75.06 to -2.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With a ≥ 2-step Improvement at Week 12 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline
Description	The Diabetic Retinopathy Disease Severity Scale (DRSS) was used to describe overall retinopathy severity. It measured the 5 levels of diabetic retinopathy ranging from absence of retinopathy to severe retinopathy (none, mild, moderate, severe, and proliferative).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received any study drug, had baseline measurement of BCVA & at least 1 post-baseline assessment of BCVA. Last observation carried forward (LOCF) method was used to impute missing data. Here "Overall Number of Participants Analyzed" = Participants who were evaluable for this outcome measure.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg)	Aflibercept 2 mg
Arm/Group Description	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	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 or Week 20 and Q8 or Q12 through week 32.	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 or REGN910-3 (6 mg:2 mg) at week 16 or 20 and Q8 through week 32.
Measure Participants	45	94	145
Number [Percentage of participants]	13.3 26.6%	21.3 21.3%	15.2 10%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using analysis of Cochran-Mantel-Haenszel model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7617
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -13.5 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Analysis was performed using analysis of Cochran-Mantel-Haenszel model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2268
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 95%; - 4.1 to 16.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With a ≥ 2-step Improvement at Week 36 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline
Description	The Diabetic Retinopathy Disease Severity Scale (DRSS) was used to describe overall retinopathy severity. It measured the 5 levels of diabetic retinopathy ranging from absence of retinopathy to severe retinopathy (none, mild, moderate, severe, and proliferative).
Time Frame	Baseline, Week 36

Outcome Measure Data

Analysis Population Description

FAS secondary randomization set was used. Overall Number of Participants Analyzed = Participants who were evaluable for this outcome measure.

Arm/Group Title	REGN910-3 (3 mg: 2 mg)	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q8	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
Arm/Group Description	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	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.	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.	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 16 and Q8 through week 32.	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.	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.
Measure Participants	45	44	50	46	47	48
Number [Percentage of participants]	26.7 53.4%	34.1 34.1%	34.0 22.4%	26.1 8.6%	25.5 NaN	35.4 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (3 mg: 2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8896
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -20.4 to 17.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5021
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	6.4
	Confidence Interval	(2-Sided) 95%; -12.6 to 25.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5273
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	6.0
	Confidence Interval	(2-Sided) 95%; -12.8 to 24.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8683
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -19.7 to 16.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8, Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3546
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 95%; -9.8 to 27.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	REGN910-3 (6 mg:2 mg), Aflibercept 2 mg
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9801
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -19.0 to 19.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Aflibercept 2 mg, Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12
	Comments	Difference with Confidence Interval was calculated using Mantel-Haenszel weighting scheme adjusted by BCVA stratification variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3528
	Comments	Threshold for significance at 0.05 level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	difference in percentages
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 95%; -9.9 to 27.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 36) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Arm/Group Title	REGN910-3 (3 mg: 2 mg)		REGN910-3 (6 mg:2 mg)		Aflibercept 2 mg
Arm/Group Description	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.		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 or Week 20 and Q8 or Q12 through week 32.		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 or REGN910-3 (6 mg:2 mg) at week 16 or 20 and Q8 through week 32.
All Cause Mortality
	REGN910-3 (3 mg: 2 mg)		REGN910-3 (6 mg:2 mg)		Aflibercept 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/50 (10%)		0/100 (0%)		4/152 (2.6%)
Serious Adverse Events
	REGN910-3 (3 mg: 2 mg)		REGN910-3 (6 mg:2 mg)		Aflibercept 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/50 (12%)		18/100 (18%)		31/152 (20.4%)
Cardiac disorders
Acute coronary syndrome	0/50 (0%)	0	0/100 (0%)	0	2/152 (1.3%)	2
Angina pectoris	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Angina unstable	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Cardiac arrest	1/50 (2%)	1	0/100 (0%)	0	0/152 (0%)	0
Cardiac failure acute	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Cardiac failure congestive	0/50 (0%)	0	3/100 (3%)	3	3/152 (2%)	3
Cardiomegaly	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Cardiorenal syndrome	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Coronary artery disease	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Myocardial infarction	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Ventricular tachycardia	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Ear and labyrinth disorders
Vertigo	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Eye disorders
Iridocyclitis	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Retinal artery occlusion	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Intestinal varices	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Nausea	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Vomiting	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
General disorders
Death	2/50 (4%)	2	0/100 (0%)	0	0/152 (0%)	0
Oedema peripheral	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Hepatobiliary disorders
Cholelithiasis	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Infections and infestations
Bacterial sepsis	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Cellulitis	1/50 (2%)	1	1/100 (1%)	1	3/152 (2%)	3
Diabetic foot infection	1/50 (2%)	1	0/100 (0%)	0	0/152 (0%)	0
Diverticulitis	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Endocarditis staphylococcal	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Extradural abscess	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Gangrene	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Gastric infection	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Gastroenteritis	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Localised infection	0/50 (0%)	0	1/100 (1%)	1	1/152 (0.7%)	1
Osteomyelitis	1/50 (2%)	1	1/100 (1%)	2	1/152 (0.7%)	1
Pneumonia	0/50 (0%)	0	1/100 (1%)	2	0/152 (0%)	0
Septic arthritis staphylococcal	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Staphylococcal infection	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Injury, poisoning and procedural complications
Ankle fracture	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Burns second degree	0/50 (0%)	0	1/100 (1%)	1	1/152 (0.7%)	1
Burns third degree	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Fall	0/50 (0%)	0	2/100 (2%)	2	1/152 (0.7%)	1
Femur fracture	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Mental status changes postoperative	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Investigations
Troponin increased	1/50 (2%)	1	0/100 (0%)	0	0/152 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	2
Diabetic ketoacidosis	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Hyperglycaemia	0/50 (0%)	0	1/100 (1%)	1	1/152 (0.7%)	1
Hypokalaemia	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Lactic acidosis	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Type 1 diabetes mellitus	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	2
Musculoskeletal and connective tissue disorders
Arthritis	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Muscular weakness	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer stage ii	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Intraductal proliferative breast lesion	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Large intestine benign neoplasm	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Nervous system disorders
Cerebral haemorrhage	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Cerebrovascular accident	1/50 (2%)	1	0/100 (0%)	0	0/152 (0%)	0
Guillain-Barre syndrome	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Hepatic encephalopathy	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Syncope	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Transient ischaemic attack	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Psychiatric disorders
Mental status changes	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/50 (0%)	0	1/100 (1%)	1	2/152 (1.3%)	2
Chronic kidney disease	0/50 (0%)	0	0/100 (0%)	0	3/152 (2%)	3
End stage renal disease	0/50 (0%)	0	1/100 (1%)	2	0/152 (0%)	0
Nephrotic syndrome	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Renal failure	0/50 (0%)	0	0/100 (0%)	0	2/152 (1.3%)	2
Renal impairment	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Reproductive system and breast disorders
Penile oedema	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Dyspnoea	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Epistaxis	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Pleural effusion	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Respiratory depression	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	1/50 (2%)	1	0/100 (0%)	0	2/152 (1.3%)	2
Vascular disorders
Arteriosclerosis	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Embolism	1/50 (2%)	1	0/100 (0%)	0	0/152 (0%)	0
Hypertensive emergency	0/50 (0%)	0	1/100 (1%)	1	0/152 (0%)	0
Hypotension	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Lymphoedema	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Orthostatic hypotension	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Peripheral arterial occlusive disease	0/50 (0%)	0	0/100 (0%)	0	1/152 (0.7%)	1
Other (Not Including Serious) Adverse Events
	REGN910-3 (3 mg: 2 mg)		REGN910-3 (6 mg:2 mg)		Aflibercept 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/50 (36%)		42/100 (42%)		55/152 (36.2%)
Eye disorders
Conjunctival haemorrhage	5/50 (10%)	6	3/100 (3%)	4	13/152 (8.6%)	16
Dry eye	0/50 (0%)	0	5/100 (5%)	5	1/152 (0.7%)	1
Eye pain	3/50 (6%)	4	3/100 (3%)	3	4/152 (2.6%)	4
Vitreous detachment	1/50 (2%)	1	8/100 (8%)	10	8/152 (5.3%)	8
Gastrointestinal disorders
Nausea	0/50 (0%)	0	5/100 (5%)	5	1/152 (0.7%)	1
Infections and infestations
Urinary tract infection	1/50 (2%)	1	5/100 (5%)	7	7/152 (4.6%)	8
Viral upper respiratory tract infection	3/50 (6%)	3	3/100 (3%)	4	5/152 (3.3%)	6
Investigations
Blood pressure increased	2/50 (4%)	2	7/100 (7%)	8	10/152 (6.6%)	14
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	3/50 (6%)	3	0/100 (0%)	0	1/152 (0.7%)	1
Nervous system disorders
Neuropathy peripheral	3/50 (6%)	3	0/100 (0%)	0	0/152 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/50 (0%)	0	7/100 (7%)	7	4/152 (2.6%)	4
Vascular disorders
Hypertension	4/50 (8%)	4	14/100 (14%)	15	19/152 (12.5%)	19

Limitations/Caveats

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