Trial Outcomes & Findings for Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema (NCT NCT02712008)

NCT ID: NCT02712008

Last Updated: 2018-10-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

302 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2018-10-03

Participant Flow

The study was conducted at 70 sites in US. A total of 438 participants were screened in the study.

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.

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.	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.	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 week 16 and Q8 through week 32.	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.	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.
Baseline (Day 1) up to Week 12 STARTED	50	100	152	0	0	0	0	0
Baseline (Day 1) up to Week 12 COMPLETED	46	97	148	0	0	0	0	0
Baseline (Day 1) up to Week 12 NOT COMPLETED	4	3	4	0	0	0	0	0
From Week 12 up to Week 36 STARTED	45	0	0	44	52	46	48	49
From Week 12 up to Week 36 COMPLETED	44	0	0	42	50	46	43	45
From Week 12 up to Week 36 NOT COMPLETED	1	0	0	2	2	0	5	4

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.	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.	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.	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.	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.
Baseline (Day 1) up to Week 12 Death	3	0	0	0	0	0	0
Baseline (Day 1) up to Week 12 Withdrawal by Subject	0	2	1	0	0	0	0
Baseline (Day 1) up to Week 12 Lost to Follow-up	1	0	2	0	0	0	0
Baseline (Day 1) up to Week 12 Protocol Violation	0	0	1	0	0	0	0
Baseline (Day 1) up to Week 12 Other Unspecified	0	1	0	0	0	0	0
From Week 12 up to Week 36 Adverse Event	0	0	0	0	1	0	2
From Week 12 up to Week 36 Death	1	0	0	0	0	1	0
From Week 12 up to Week 36 Lost to Follow-up	0	0	0	1	0	1	0
From Week 12 up to Week 36 Physician Decision	0	0	0	1	1	0	0
From Week 12 up to Week 36 Withdrawal by Subject	0	0	0	0	0	3	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	REGN910-3 (3 mg: 2 mg) n=50 Participants 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	REGN910-3 (6 mg:2 mg) n=100 Participants 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.	Aflibercept 2 mg n=152 Participants 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 n=302 Participants Total of all reporting groups
Age, Continuous	62.5 years STANDARD_DEVIATION 9.12 • n=5 Participants	62.5 years STANDARD_DEVIATION 10.36 • n=7 Participants	59.5 years STANDARD_DEVIATION 10.20 • n=5 Participants	61.0 years STANDARD_DEVIATION 10.16 • n=4 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	49 Participants n=7 Participants	68 Participants n=5 Participants	138 Participants n=4 Participants
Sex: Female, Male Male	29 Participants n=5 Participants	51 Participants n=7 Participants	84 Participants n=5 Participants	164 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	21 Participants n=7 Participants	26 Participants n=5 Participants	53 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	44 Participants n=5 Participants	78 Participants n=7 Participants	125 Participants n=5 Participants	247 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	7 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Black or African American	11 Participants n=5 Participants	8 Participants n=7 Participants	19 Participants n=5 Participants	38 Participants n=4 Participants
Race (NIH/OMB) White	37 Participants n=5 Participants	87 Participants n=7 Participants	121 Participants n=5 Participants	245 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	7 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: 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.

Outcome measures

Outcome measures
Measure	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.	REGN910-3 (3 mg: 2 mg) n=47 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=150 Participants 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.	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 week 16 and Q8 through week 32.	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.	REGN910-3 (6 mg:2 mg) n=99 Participants 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.
Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 12	—	6.8 Letters correctly read Standard Deviation 7.30	8.8 Letters correctly read Standard Deviation 9.71	—	—	8.5 Letters correctly read Standard Deviation 6.89

PRIMARY outcome

Timeframe: Baseline, Week 36

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8 n=49 Participants 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.	REGN910-3 (3 mg: 2 mg) n=45 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=52 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8 n=46 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12 n=48 Participants 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.	REGN910-3 (6 mg:2 mg) n=44 Participants 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.
Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 36	11.9 Letters correctly read Standard Deviation 12.01	9.8 Letters correctly read Standard Deviation 9.92	8.5 Letters correctly read Standard Deviation 7.74	8.7 Letters correctly read Standard Deviation 10.65	10.0 Letters correctly read Standard Deviation 10.37	10.3 Letters correctly read Standard Deviation 8.20

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	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.	REGN910-3 (3 mg: 2 mg) n=46 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=150 Participants 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.	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 week 16 and Q8 through week 32.	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.	REGN910-3 (6 mg:2 mg) n=99 Participants 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.
Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 12	—	-169.4 Microns Standard Deviation 155.86	-174.6 Microns Standard Deviation 160.36	—	—	-184.0 Microns Standard Deviation 143.69

SECONDARY outcome

Timeframe: Baseline, Week 36

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

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.

Outcome measures

Outcome measures
Measure	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8 n=49 Participants 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.	REGN910-3 (3 mg: 2 mg) n=44 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=52 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8 n=46 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12 n=48 Participants 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.	REGN910-3 (6 mg:2 mg) n=44 Participants 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.
Change From Baseline in Central Sub-field Retinal Thickness (CST) Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) at Week 36	-203.7 Microns Standard Deviation 163.08	-210.4 Microns Standard Deviation 164.06	-193.7 Microns Standard Deviation 158.29	-161.9 Microns Standard Deviation 125.99	-210.6 Microns Standard Deviation 202.15	-223.4 Microns Standard Deviation 145.35

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	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.	REGN910-3 (3 mg: 2 mg) n=45 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=145 Participants 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.	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 week 16 and Q8 through week 32.	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.	REGN910-3 (6 mg:2 mg) n=94 Participants 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.
Percentage of Participants With a ≥ 2-step Improvement at Week 12 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline	—	13.3 Percentage of participants	15.2 Percentage of participants	—	—	21.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 36

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

Outcome measures

Outcome measures
Measure	Aflibercept 2 mg Q4 to REGN910-3 (6 mg:2 mg) Q8 n=48 Participants 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.	REGN910-3 (3 mg: 2 mg) n=45 Participants 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	REGN910-3 (6 mg:2 mg) Q4 to REGN910-3 (6 mg:2 mg) Q12 n=50 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q8 n=46 Participants 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.	Aflibercept 2 mg Q4 to Aflibercept 2 mg Q12 n=47 Participants 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.	REGN910-3 (6 mg:2 mg) n=44 Participants 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.
Percentage of Participants With a ≥ 2-step Improvement at Week 36 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline	35.4 Percentage of participants	26.7 Percentage of participants	34.0 Percentage of participants	26.1 Percentage of participants	25.5 Percentage of participants	34.1 Percentage of participants

Adverse Events

REGN910-3 (3 mg: 2 mg)

Serious events: 6 serious events

Other events: 18 other events

Deaths: 5 deaths

REGN910-3 (6 mg:2 mg)

Serious events: 18 serious events

Other events: 42 other events

Deaths: 0 deaths

Aflibercept 2 mg

Serious events: 31 serious events

Other events: 55 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	REGN910-3 (3 mg: 2 mg) n=50 participants at risk 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.	REGN910-3 (6 mg:2 mg) n=100 participants at risk 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.	Aflibercept 2 mg n=152 participants at risk 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.
Eye disorders Conjunctival haemorrhage	10.0% 5/50 • Number of events 6 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	3.0% 3/100 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	8.6% 13/152 • Number of events 16 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Eye disorders Dry eye	0.00% 0/50 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	5.0% 5/100 • Number of events 5 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.66% 1/152 • Number of events 1 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Eye disorders Eye pain	6.0% 3/50 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	3.0% 3/100 • Number of events 3 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	2.6% 4/152 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Eye disorders Vitreous detachment	2.0% 1/50 • Number of events 1 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	8.0% 8/100 • Number of events 10 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	5.3% 8/152 • Number of events 8 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Gastrointestinal disorders Nausea	0.00% 0/50 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	5.0% 5/100 • Number of events 5 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.66% 1/152 • Number of events 1 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Infections and infestations Urinary tract infection	2.0% 1/50 • Number of events 1 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	5.0% 5/100 • Number of events 7 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	4.6% 7/152 • Number of events 8 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Infections and infestations Viral upper respiratory tract infection	6.0% 3/50 • Number of events 3 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	3.0% 3/100 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	3.3% 5/152 • Number of events 6 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Investigations Blood pressure increased	4.0% 2/50 • Number of events 2 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	7.0% 7/100 • Number of events 8 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	6.6% 10/152 • Number of events 14 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	6.0% 3/50 • Number of events 3 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.00% 0/100 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.66% 1/152 • Number of events 1 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Nervous system disorders Neuropathy peripheral	6.0% 3/50 • Number of events 3 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.00% 0/100 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	0.00% 0/152 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/50 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	7.0% 7/100 • Number of events 7 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	2.6% 4/152 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).
Vascular disorders Hypertension	8.0% 4/50 • Number of events 4 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	14.0% 14/100 • Number of events 15 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).	12.5% 19/152 • Number of events 19 • 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. Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (Baseline up to Week 36).

Additional Information

Clinical Trial Management

Regeneron Pharmaceuticals, Inc.

Phone: 844-734-6643

Email: [email protected]

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