VIVID-DME: Intravitreal Aflibercept Injection in Vision Impairment Due to DME

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01331681
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 406
• Locations: 90
• Arms: 3
• Duration (Months): 46
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To determine the efficacy of intravitreally (IVT) administered VEGF Trap-Eye on the best-corrected visual acuity (BCVA) assessed by the early treatment diabetic retinopathy study (ETDRS) chart in subjects with diabetic macular edema (DME) with central involvement

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus; Macular Edema	Biological: VEGF Trap-Eye (BAY86-5321); Biological: VEGF Trap-Eye (BAY86-5321); Procedure: Macular Laser Photocoagulation (Control)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 406 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Masked, Active Controlled, Phase III Study of the Efficacy and Safety of Repeated Doses of Intravitreal VEGF Trap-Eye in Subjects With Diabetic Macular Edema
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intravitreal Aflibercept Injection 2Q4 Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Biological: VEGF Trap-Eye (BAY86-5321); Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).
Experimental: Intravitreal Aflibercept Injection 2Q8 Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Biological: VEGF Trap-Eye (BAY86-5321); Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).
Active Comparator: Macular Laser Photocoagulation (Control) Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.	Procedure: Macular Laser Photocoagulation (Control); Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) [Baseline up to Week 52]

   Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.

Secondary Outcome Measures

1. Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF [Baseline up to Week 52]

   Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.

2. Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF [Baseline up to Week 52]

   Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.

3. Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF [Baseline up to Week 52]

   Baseline ETDRS DRSS: None (level 10); Mild to moderate nonproliferative DR (levels 14, 15, 20, 35, and 43); Moderately severe/severe nonproliferative DR (levels 47 and 53); Mild/moderate/high-risk/advanced proliferative DR (levels 61, 65, 71,75, 81, and 85)

4. Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF [Baseline up to Week 52]

5. Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF [Baseline up to Week 52]

   The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales that are all scored from 0-100. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf.

6. Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF [Baseline up to Week 52]

   The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales that are all scored from 0-100. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adults ≥ 18 years with type 1 or 2 diabetes mellitus

• Subjects with DME secondary to diabetes mellitus involving the center of the macula in the study eye

• Decrease in vision determined to be primarily the result of DME in the study eye

• BCVA ETDRS letter score of 73 to 24 (20/40 to 20/320) in the study eye

Exclusion Criteria:

• Laser photocoagulation (panretinal or macular) in the study eye within 90 days of Day 1

• More than 2 previous macular laser treatments in the study eye

• Previous use of intraocular or periocular corticosteroids in the study eye within 120 days of Day 1

• Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium, bevacizumab, ranibizumab etc.) within 90 days of Day 1

• Active proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR

• Uncontrolled diabetes mellitus, as defined by HbA1c > 12%

• Only 1 functional eye even if that eye is otherwise eligible for the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chatswood	New South Wales	Australia	2067
2		Sydney	New South Wales	Australia	2000
3		Westmead	New South Wales	Australia	2145
4		East Melbourne	Victoria	Australia	3002
5		Prahran	Victoria	Australia
6		Nedlands	Western Australia	Australia	6009
7		Parramatta		Australia	2150
8		Linz	Oberösterreich	Austria	4021
9		Linz		Austria	4021
10		Wien		Austria	1090
11		Hradec Kralove		Czech Republic	500 05
12		Olomouc		Czech Republic	77520
13		Ostrava		Czech Republic	708 52
14		Praha 10		Czech Republic	100 34
15		Zlin		Czech Republic	760 01
16		Glostrup		Denmark	2600
17		Odense C		Denmark	5000
18		Århus C		Denmark	8000
19		Bordeaux		France	33076
20		Creteil Cedex		France	94010
21		Lyon		France	69003
22		Marseille		France	13008
23		Nantes Cedex		France	44093
24		Paris		France	75006
25		Paris		France	75010
26		Paris		France	75015
27		Freiburg	Baden-Württemberg	Germany	79106
28		Heidelberg	Baden-Württemberg	Germany	69120
29		Mannheim	Baden-Württemberg	Germany	68167
30		Tübingen	Baden-Württemberg	Germany	72076
31		München	Bayern	Germany	81675
32		Darmstadt	Hessen	Germany	64297
33		Göttingen	Niedersachsen	Germany	37075
34		Aachen	Nordrhein-Westfalen	Germany	52074
35		Bochum	Nordrhein-Westfalen	Germany	44892
36		Bonn	Nordrhein-Westfalen	Germany	53105
37		Köln	Nordrhein-Westfalen	Germany	50924
38		Münster	Nordrhein-Westfalen	Germany	48145
39		Ludwigshafen	Rheinland-Pfalz	Germany	67063
40		Mainz	Rheinland-Pfalz	Germany	55131
41		Chemnitz	Sachsen	Germany	09116
42		Dresden	Sachsen	Germany	06067
43		Leipzig	Sachsen	Germany	04103
44		Kiel	Schleswig-Holstein	Germany	24105
45		Berlin		Germany	12203
46		Budapest		Hungary	1083
47		Budapest		Hungary	1106
48		Budapest		Hungary	1133
49		Debrecen		Hungary	4032
50		Veszprem		Hungary	8200
51		Zalaegerszeg		Hungary	H-8900
52		Ancona		Italy	60126
53		Milano		Italy	20122
54		Milano		Italy	20157
55		Padova		Italy	35128
56		Roma		Italy	00133
57		Roma		Italy	00198
58		Nagoya	Aichi	Japan	466-8560
59		Nagoya	Aichi	Japan	467-8602
60		Asahikwa	Hokkaido	Japan	078-8510
61		Sapporo	Hokkaido	Japan	060-8648
62		Kawasaki	Kanagawa	Japan	216-8511
63		Sendai	Miyagi	Japan	980-8574
64		Matsumoto	Nagano	Japan	390-8621
65		Yufu	Oita	Japan	879-5593
66		Hirakata	Osaka	Japan	573-1191
67		Chiyoda-ku	Tokyo	Japan	101-8309
68		Itabashi-ku	Tokyo	Japan	173-8606
69		Mitaka	Tokyo	Japan	181-8611
70		Shinjuku-ku	Tokyo	Japan	162-8666
71		Akita		Japan	010-8543
72		Chiba		Japan	260-8677
73		Fukuoka		Japan	812-8582
74		Nagasaki		Japan	852-8501
75		Osaka		Japan	545-8586
76		Wakayama		Japan	641-8510
77		Bialystok		Poland	15-276
78		Bytom		Poland	41-902
79		Wroclaw		Poland	50-556
80		Wroclaw		Poland	51-124
81		Santiago de Compostela	A Coruña	Spain	15706
82		Oviedo	Asturias	Spain	33012
83		San Cugat del Vallès	Barcelona	Spain	08190
84		Alicante		Spain	03016
85		Barcelona		Spain	08036
86		Pamplona		Spain	31008
87		Valencia		Spain	46015
88		Changhua City	Changhua	Taiwan	500
89		Kaohsiung		Taiwan	81362
90		Taipei		Taiwan

Sponsors and Collaborators

• Bayer
• Regeneron Pharmaceuticals

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01331681
• Other Study ID Numbers: 91745; 2010-022364-12
• First Posted: Apr 8, 2011
• Last Update Posted: Apr 19, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Bayer: Diabetic Macular Edema (DME); VEGF Trap-Eye; Best-corrected visual acuity (BCVA)
• Additional relevant MeSH terms: Macular Edema; Edema; Aflibercept

Study Results

Participant Flow

Recruitment Details	Participants with diabetic macular edema (DME) secondary to diabetes mellitus involving the center of the macula in the study eye could participate in the study. The study was conducted at 73 study centers in Japan, European Countries and Australia between 09 May 2011(first participant first visit) and 30 Mar 2015 (last participant last visit).
Pre-assignment Detail	Of 604 participants who were screened for inclusion in the study, 406 were randomized, and 404 received treatment.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF [vascular endothelial growth factor] Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Period Title: Overall Study
STARTED	136	135	135
Participants Received Treatment	136	135	133
Completed Week 52	125	121	115
Completed Week 100	115	110	105
Completed Week 148	101	101	100
COMPLETED	101	101	100
NOT COMPLETED	35	34	35

Baseline Characteristics

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control	Total
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.	Total of all reporting groups
Overall Participants	136	135	133	404
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.6 (8.6)	64.2 (7.8)	63.9 (8.6)	63.6 (8.3)
Sex: Female, Male (Count of Participants)
Female	53 39%	47 34.8%	54 40.6%	154 38.1%
Male	83 61%	88 65.2%	79 59.4%	250 61.9%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF)
Description	Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants who received any study treatment, had a baseline measurement of BCVA, and had at least 1 post-baseline assessment of BCVA.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	136	135	132
Mean (Standard Deviation) [Letters correctly read]	10.5 (9.55)	10.7 (9.32)	1.2 (10.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value was below the significance level of 0.025, the fixed sequence testing did continue with the first secondary endpoint.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.3
	Confidence Interval	(2-Sided) 97.5%; 6.5 to 12.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least square (LS) mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value was below the significance level of 0.025, the fixed sequence testing did continue with the first secondary endpoint.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.1
	Confidence Interval	(2-Sided) 97.5%; 6.3 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

2. Secondary Outcome

Title	Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF
Description	Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	136	135	132
Number [Percentage of participants]	54.4 40%	53.3 39.5%	25.8 19.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Probability to gain >= 10 letters identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the second secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	28.7
	Confidence Interval	(2-Sided) 97.5%; 15.8 to 41.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Probability to gain >= 10 letters identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the second secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	27.5
	Confidence Interval	(2-Sided) 97.5%; 14.6 to 40.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

3. Secondary Outcome

Title	Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF
Description	Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	136	135	132
Number [Percentage of participants]	32.4 23.8%	33.3 24.7%	9.1 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Probability to gain >= 15 letters identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the third secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	23.3
	Confidence Interval	(2-Sided) 97.5%; 12.6 to 33.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Probability to gain >= 15 letters identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the third secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	24.2
	Confidence Interval	(2-Sided) 97.5%; 13.5 to 34.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

4. Secondary Outcome

Title	Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF
Description	Baseline ETDRS DRSS: None (level 10); Mild to moderate nonproliferative DR (levels 14, 15, 20, 35, and 43); Moderately severe/severe nonproliferative DR (levels 47 and 53); Mild/moderate/high-risk/advanced proliferative DR (levels 61, 65, 71,75, 81, and 85)
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	81	83	80
Number [Percentage of participants]	33.3 24.5%	27.7 20.5%	7.5 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Probability to improve by >= 2 steps identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fourth secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	25.8
	Confidence Interval	(2-Sided) 97.5%; 12.2 to 39.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Probability to improve by >= 2 steps identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fourth secondary endpoint.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratifying by geographic region (Japan vs non-Japan).
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	19.3
	Confidence Interval	(2-Sided) 97.5%; 6.6 to 32.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

5. Secondary Outcome

Title	Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	135	135	132
Mean (Standard Deviation) [micrometer]	-195.0 (146.59)	-192.4 (149.89)	-66.2 (138.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fifth secondary endpoint.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-157.0
	Confidence Interval	(2-Sided) 97.5%; -190.9 to -123.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fifth secondary endpoint.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-142.8
	Confidence Interval	(2-Sided) 97.5%; -179.3 to -106.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.

6. Secondary Outcome

Title	Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF
Description	The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales that are all scored from 0-100. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	128	134	120
Mean (Standard Deviation) [Scores on a scale]	5.73 (18.932)	5.29 (19.058)	3.54 (16.768)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2208
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value is not below of 0.025, the fixed sequence testing stops here. The sixth secondary endpoint cannot be tested confirmatory.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.41
	Confidence Interval	(2-Sided) 97.5%; -2.01 to 6.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5537
	Comments	Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value is not below of 0.025, the fixed sequence testing stops here. The sixth secondary endpoint cannot be tested confirmatory.
	Method	ANCOVA
	Comments	Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 97.5%; -5.79 to 3.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

7. Secondary Outcome

Title	Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF
Description	The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales that are all scored from 0-100. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure.

Arm/Group Title	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Control
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).	Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
Measure Participants	128	134	120
Mean (Standard Deviation) [Scores on a scale]	0.94 (16.487)	5.32 (18.475)	2.26 (15.923)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q4, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5138
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.19
	Confidence Interval	(2-Sided) 97.5%; -5.29 to 2.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intravitreal Aflibercept Injection 2Q8, Control
	Comments	Hypothesis: Mean change identical in both groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8498
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 97.5%; -4.79 to 4.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Adverse Events

Time Frame	For each subject from his first study drug injection until 30 days after the last study drug injection at the latest up to termination visit at Week 148
Arm/Group Title	Intravitreal Aflibercept Injection 2Q4		Intravitreal Aflibercept Injection 2Q8		Macular Laser Photocoagulation (Control)
Arm/Group Description	Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).		Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).		Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks. During year 3 laser patients could receive IAI as needed (PRN) .
All Cause Mortality
	Intravitreal Aflibercept Injection 2Q4		Intravitreal Aflibercept Injection 2Q8		Macular Laser Photocoagulation (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Intravitreal Aflibercept Injection 2Q4		Intravitreal Aflibercept Injection 2Q8		Macular Laser Photocoagulation (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/ (NaN)		60/ (NaN)		51/ (NaN)
Blood and lymphatic system disorders
Anaemia	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	1
Immune thrombocytopenic purpura	1/136 (0.7%)	2	0/135 (0%)	0	0/133 (0%)	0
Neutropenia	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Acute myocardial infarction	2/136 (1.5%)	2	0/135 (0%)	0	3/133 (2.3%)	3
Angina unstable	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Arrhythmia	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Atrioventricular block complete	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Bundle branch block right	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cardiac disorder	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cardiac failure	1/136 (0.7%)	1	2/135 (1.5%)	2	2/133 (1.5%)	2
Cardiac failure acute	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cardiac failure chronic	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	2
Cardiac failure congestive	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cardiac sarcoidosis	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cardiac valve disease	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cardiogenic shock	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Coronary artery disease	2/136 (1.5%)	3	0/135 (0%)	0	1/133 (0.8%)	1
Coronary artery stenosis	2/136 (1.5%)	2	0/135 (0%)	0	0/133 (0%)	0
Hypertensive heart disease	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Ischaemic cardiomyopathy	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Left ventricular failure	1/136 (0.7%)	2	0/135 (0%)	0	0/133 (0%)	0
Mitral valve stenosis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Myocardial infarction	4/136 (2.9%)	4	1/135 (0.7%)	1	1/133 (0.8%)	1
Myocardial ischaemia	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Ventricular arrhythmia	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Ventricular tachycardia	1/136 (0.7%)	2	0/135 (0%)	0	0/133 (0%)	0
Ear and labyrinth disorders
Deafness	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Vertigo	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Endocrine disorders
Toxic nodular goitre	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Eye disorders
Cataract	5/136 (3.7%)	8	7/135 (5.2%)	11	2/133 (1.5%)	2
Cataract subcapsular	1/136 (0.7%)	1	2/135 (1.5%)	2	0/133 (0%)	0
Diabetic retinopathy	0/136 (0%)	0	0/135 (0%)	0	2/133 (1.5%)	2
Iridocyclitis	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Macular degeneration	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Macular fibrosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Macular hole	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Optic atrophy	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Posterior capsule opacification	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Retinal artery occlusion	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Retinal detachment	0/136 (0%)	0	2/135 (1.5%)	2	1/133 (0.8%)	1
Retinal exudates	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Retinal neovascularisation	1/136 (0.7%)	1	0/135 (0%)	0	3/133 (2.3%)	4
Retinal vascular disorder	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	2
Retinopathy proliferative	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Vitreous haemorrhage	4/136 (2.9%)	5	1/135 (0.7%)	1	2/133 (1.5%)	4
Gastrointestinal disorders
Abdominal pain upper	1/136 (0.7%)	1	1/135 (0.7%)	1	0/133 (0%)	0
Colitis ischaemic	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Enterocolitis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Gastric ulcer	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Ileus	0/136 (0%)	0	2/135 (1.5%)	2	0/133 (0%)	0
Inguinal hernia	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Intestinal obstruction	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Rectal haemorrhage	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Reflux gastritis	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
General disorders
Chest pain	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Death	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Device failure	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	2
Generalised oedema	0/136 (0%)	0	1/135 (0.7%)	2	0/133 (0%)	0
Injection site injury	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Oedema peripheral	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cholelithiasis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Hepatic cirrhosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Infections and infestations
Cellulitis	0/136 (0%)	0	2/135 (1.5%)	2	2/133 (1.5%)	2
Cholecystitis infective	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Endophthalmitis	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Gangrene	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Gastroenteritis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Infected dermal cyst	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Infected skin ulcer	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Osteomyelitis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Pilonidal cyst	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Pneumonia	1/136 (0.7%)	1	3/135 (2.2%)	3	0/133 (0%)	0
Pyelonephritis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Salmonellosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Sepsis	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	1
Urinary tract infection	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	2
Injury, poisoning and procedural complications
Ankle fracture	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Brain contusion	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Brain herniation	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Femoral neck fracture	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Femur fracture	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Fracture	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Head injury	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Humerus fracture	3/136 (2.2%)	3	1/135 (0.7%)	1	0/133 (0%)	0
Joint dislocation	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Lower limb fracture	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Meniscus injury	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Rib fracture	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Spinal fracture	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Subdural haematoma	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Thermal burn	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Tibia fracture	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Traumatic arthrosis	1/136 (0.7%)	2	0/135 (0%)	0	0/133 (0%)	0
Traumatic fracture	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Investigations
Catheterisation cardiac	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Electrocardiogram ST segment depression	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Visual acuity tests abnormal	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/136 (0.7%)	2	2/135 (1.5%)	2	1/133 (0.8%)	2
Diabetic ketoacidosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Fluid retention	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Hyperglycaemia	0/136 (0%)	0	2/135 (1.5%)	2	2/133 (1.5%)	2
Hypoglycaemia	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Ketoacidosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Type 2 diabetes mellitus	1/136 (0.7%)	2	0/135 (0%)	0	0/133 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Arthropathy	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Intervertebral disc protrusion	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Lumbar spinal stenosis	0/136 (0%)	0	0/135 (0%)	0	2/133 (1.5%)	2
Metatarsalgia	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Musculoskeletal disorder	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Neck pain	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Osteoarthritis	2/136 (1.5%)	2	0/135 (0%)	0	0/133 (0%)	0
Polymyalgia rheumatica	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	1
Rotator cuff syndrome	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Spinal column stenosis	0/136 (0%)	0	1/135 (0.7%)	2	0/133 (0%)	0
Spinal pain	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Spondylolisthesis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Synovitis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Tenosynovitis stenosans	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Adrenal neoplasm	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Anaplastic astrocytoma	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
B-cell lymphoma	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Bladder neoplasm	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Breast cancer	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Colon cancer	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Lung neoplasm	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Lung neoplasm malignant	1/136 (0.7%)	1	1/135 (0.7%)	1	0/133 (0%)	0
Metastases to liver	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	1
Metastases to lung	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	1
Neoplasm malignant	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Pancreatic carcinoma stage IV	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Prostate cancer	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Prostate cancer stage I	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Prostate cancer stage III	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Renal neoplasm	2/136 (1.5%)	2	0/135 (0%)	0	1/133 (0.8%)	1
Uterine leiomyoma	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Nervous system disorders
Brain stem infarction	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Cauda equina syndrome	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Cerebral atrophy	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cerebral haematoma	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Cerebral haemorrhage	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cerebrovascular accident	4/136 (2.9%)	4	1/135 (0.7%)	1	1/133 (0.8%)	1
Ischaemic stroke	2/136 (1.5%)	2	0/135 (0%)	0	1/133 (0.8%)	1
Loss of consciousness	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Nerve compression	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Peripheral sensorimotor neuropathy	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Syncope	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Psychiatric disorders
Depression	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	2
Suicide attempt	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Renal and urinary disorders
Acute kidney injury	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Chronic kidney disease	1/136 (0.7%)	1	1/135 (0.7%)	1	0/133 (0%)	0
Nephrolithiasis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Renal artery stenosis	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Renal failure	1/136 (0.7%)	1	2/135 (1.5%)	2	0/133 (0%)	0
Renal impairment	0/136 (0%)	0	1/135 (0.7%)	2	0/133 (0%)	0
Stress urinary incontinence	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/136 (0%)	0	1/135 (0.7%)	1	2/133 (1.5%)	2
Uterine polyp	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Uterine prolapse	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Dyspnoea	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Hydrothorax	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Pleural effusion	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Pulmonary embolism	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Respiratory failure	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Sleep apnoea syndrome	1/136 (0.7%)	1	1/135 (0.7%)	1	0/133 (0%)	0
Skin and subcutaneous tissue disorders
Dermal cyst	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Diabetic foot	1/136 (0.7%)	2	0/135 (0%)	0	2/133 (1.5%)	2
Psoriasis	0/136 (0%)	0	0/135 (0%)	0	2/133 (1.5%)	3
Skin ulcer	0/136 (0%)	0	1/135 (0.7%)	1	2/133 (1.5%)	2
Surgical and medical procedures
Arteriovenous shunt operation	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Cataract operation	3/136 (2.2%)	3	1/135 (0.7%)	1	2/133 (1.5%)	3
Hip arthroplasty	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Osteosynthesis	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Peripheral artery bypass	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Radical prostatectomy	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Transurethral prostatectomy	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Vitrectomy	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Vascular disorders
Arterial haemorrhage	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Arteriosclerosis	0/136 (0%)	0	1/135 (0.7%)	1	0/133 (0%)	0
Circulatory collapse	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Deep vein thrombosis	1/136 (0.7%)	1	0/135 (0%)	0	0/133 (0%)	0
Hypertension	1/136 (0.7%)	1	1/135 (0.7%)	1	0/133 (0%)	0
Lymphoedema	0/136 (0%)	0	0/135 (0%)	0	1/133 (0.8%)	1
Peripheral arterial occlusive disease	1/136 (0.7%)	1	2/135 (1.5%)	2	3/133 (2.3%)	3
Peripheral artery stenosis	1/136 (0.7%)	1	0/135 (0%)	0	1/133 (0.8%)	1
Peripheral ischaemia	0/136 (0%)	0	1/135 (0.7%)	1	1/133 (0.8%)	3
Other (Not Including Serious) Adverse Events
	Intravitreal Aflibercept Injection 2Q4		Intravitreal Aflibercept Injection 2Q8		Macular Laser Photocoagulation (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/136 (86%)		122/135 (90.4%)		113/133 (85%)
Blood and lymphatic system disorders
Anaemia	6/136 (4.4%)	6	3/135 (2.2%)	3	8/133 (6%)	8
Eye disorders
Cataract	31/136 (22.8%)	43	26/135 (19.3%)	37	17/133 (12.8%)	29
Cataract cortical	7/136 (5.1%)	12	6/135 (4.4%)	7	1/133 (0.8%)	3
Cataract subcapsular	11/136 (8.1%)	16	5/135 (3.7%)	6	4/133 (3%)	4
Conjunctival haemorrhage	43/136 (31.6%)	59	39/135 (28.9%)	58	17/133 (12.8%)	26
Conjunctival hyperaemia	8/136 (5.9%)	10	3/135 (2.2%)	5	9/133 (6.8%)	15
Corneal erosion	9/136 (6.6%)	11	8/135 (5.9%)	10	7/133 (5.3%)	16
Cystoid macular oedema	10/136 (7.4%)	18	20/135 (14.8%)	67	18/133 (13.5%)	51
Diabetic retinal oedema	33/136 (24.3%)	49	23/135 (17%)	44	18/133 (13.5%)	25
Eye pain	15/136 (11%)	34	10/135 (7.4%)	19	10/133 (7.5%)	15
Macular fibrosis	10/136 (7.4%)	13	12/135 (8.9%)	17	11/133 (8.3%)	14
Macular oedema	21/136 (15.4%)	41	20/135 (14.8%)	31	22/133 (16.5%)	46
Ocular hyperaemia	5/136 (3.7%)	12	7/135 (5.2%)	9	4/133 (3%)	5
Ocular hypertension	10/136 (7.4%)	21	4/135 (3%)	9	6/133 (4.5%)	7
Posterior capsule opacification	10/136 (7.4%)	15	12/135 (8.9%)	15	10/133 (7.5%)	18
Punctate keratitis	7/136 (5.1%)	13	11/135 (8.1%)	19	8/133 (6%)	14
Retinal aneurysm	14/136 (10.3%)	26	12/135 (8.9%)	26	9/133 (6.8%)	16
Retinal exudates	20/136 (14.7%)	38	22/135 (16.3%)	49	15/133 (11.3%)	32
Retinal haemorrhage	21/136 (15.4%)	35	25/135 (18.5%)	64	21/133 (15.8%)	63
Retinal vascular disorder	9/136 (6.6%)	20	8/135 (5.9%)	13	5/133 (3.8%)	10
Visual acuity reduced	33/136 (24.3%)	64	33/135 (24.4%)	81	30/133 (22.6%)	57
Vitreous detachment	9/136 (6.6%)	12	10/135 (7.4%)	11	5/133 (3.8%)	7
Vitreous floaters	13/136 (9.6%)	14	5/135 (3.7%)	7	4/133 (3%)	4
Vitreous haemorrhage	7/136 (5.1%)	14	11/135 (8.1%)	11	8/133 (6%)	12
Dry eye	5/136 (3.7%)	9	5/135 (3.7%)	7	8/133 (6%)	13
Infections and infestations
Bronchitis	12/136 (8.8%)	16	5/135 (3.7%)	5	9/133 (6.8%)	10
Conjunctivitis	14/136 (10.3%)	16	13/135 (9.6%)	20	8/133 (6%)	10
Influenza	7/136 (5.1%)	10	11/135 (8.1%)	11	13/133 (9.8%)	16
Nasopharyngitis	38/136 (27.9%)	67	39/135 (28.9%)	69	34/133 (25.6%)	62
Urinary tract infection	6/136 (4.4%)	8	11/135 (8.1%)	22	6/133 (4.5%)	11
Investigations
Blood creatinine increased	7/136 (5.1%)	8	6/135 (4.4%)	6	5/133 (3.8%)	5
Blood glucose increased	10/136 (7.4%)	13	7/135 (5.2%)	8	8/133 (6%)	10
Blood urea increased	6/136 (4.4%)	8	10/135 (7.4%)	10	6/133 (4.5%)	7
Glycosylated haemoglobin increased	12/136 (8.8%)	15	11/135 (8.1%)	12	11/133 (8.3%)	11
Intraocular pressure increased	28/136 (20.6%)	77	18/135 (13.3%)	51	16/133 (12%)	32
Visual acuity tests abnormal	19/136 (14%)	35	22/135 (16.3%)	63	32/133 (24.1%)	49
Metabolism and nutrition disorders
Diabetes mellitus	6/136 (4.4%)	6	10/135 (7.4%)	12	9/133 (6.8%)	10
Musculoskeletal and connective tissue disorders
Back pain	4/136 (2.9%)	5	3/135 (2.2%)	3	11/133 (8.3%)	11
Musculoskeletal pain	1/136 (0.7%)	1	9/135 (6.7%)	9	1/133 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	7/136 (5.1%)	10	6/135 (4.4%)	6	7/133 (5.3%)	10
Vascular disorders
Hypertension	23/136 (16.9%)	32	25/135 (18.5%)	37	24/133 (18%)	41

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

CONTRACT PARTNERS shall provide to BSP (Bayer Schering Pharma) any proposed publication or oral at least sixty (60) days prior to the intended submission or presentation. If BSP does not notify CONTRACT PARTNERS within sixty (60) days of BSP's receipt of the intended PUBLICATION, CONTRACT PARTNERS shall be free to publish. CONTRACT PARTNERS acknowledge that in case of multi-centre studies the RESULTS of the STUDY are to be published only through coordination by Bayer.