GALILEO: Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Central Retinal Vein Occlusion (CRVO)

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01012973
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 177
• Locations: 73
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To determine the efficacy of vascular endothelial growth factor (VEGF) Trap-Eye injected into the eye on vision function in subjects with macular edema as a consequence of central retinal vein occlusion

Condition or Disease	Intervention/Treatment	Phase
Retinal Vein Occlusion	Biological: Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321); Other: Sham treatment	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-masked, Sham-controlled Phase 3 Study of the Efficacy, Safety and Tolerability of Repeated Intravitreal Administration of VEGF Trap-Eye in Subjects With Macular Edema Secondary to Central Retinal Vein Occlusion (CRVO)
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Biological: Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321); Intravitreal injection. Weeks 0 to 20 of Aflibercept Injection every 4 weeks; Weeks 24 to 52 every 4 weeks PRN (pro re nata, on demand); plus additional on Week 60 and 68.; Other: Sham treatment; Sham treatment. Weeks 0 to 52 sham treatment every 4 weeks; plus additional on Week 60 and 68.
Sham Comparator: Sham treatment Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.	Other: Sham treatment; Sham treatment. Weeks 0 to 52 sham treatment every 4 weeks; plus additional on Week 60 and 68.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures [Baseline and Week 24]

   Defined study baseline range of Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision * 100); Denominator = Number of participants analyzed.

Secondary Outcome Measures

1. Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF) [Baseline and Week 24]

   Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. However, because this was assessed at the screening visit, subjects may have had a higher BCVA recorded at the baseline visit and would not have been excluded from the study.

2. Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF [Baseline and Week 24]

3. Percentage of Participants Who Developed Neovascularization During the First 24 Weeks [From baseline until Week 24]

   Formation of blood vessels in the anterior segment, optic disc, or elsewhere in the fundus up to Week 24

4. Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - LOCF [Baseline and Week 24]

   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 which are all scored from 0-100. To reach the overall composite score, each sub-scale score is averaged in order to give each sub-scale equal weight

5. Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF [Baseline and Week 24]

   EQ-5D is a quality of life questionnaire based on a scale from -0.594 (worst) to 1.00 (best).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Center-involved macular edema secondary to central retinal vein occlusion (CRVO) for no longer than 9 months with mean central subfield thickness ≥ 250 μm on optical coherence tomography (OCT)

• Adults ≥ 18 years

• Early treatment diabetic retinopathy study (ETDRS) best corrected visual acuity (BCVA) of 20/40 to 20/320 (73 to 24 letters) in the study eye

Exclusion Criteria:

• Any prior treatment with anti-VEGF agents in the study eye (Pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) or previous administration of systemic anti-angiogenic medications

• Prior panretinal laser photocoagulation or macular laser photocoagulation in the study eye

• CRVO disease duration > 9 months from date of diagnosis

• Previous use of intraocular corticosteroids in the study eye or use of periocular corticosteroids in the study eye within the 3 months prior to Day 1

• Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in either the study eye or fellow eye

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chatswood	New South Wales	Australia	2067
2		Parramatta	New South Wales	Australia	2150
3		Sydney	New South Wales	Australia	2000
4		Westmead	New South Wales	Australia	2145
5		East Melbourne	Victoria	Australia	3002
6		Nedlands	Western Australia	Australia	6009
7		Innsbruck		Austria	6020
8		Linz		Austria	4021
9		Wien		Austria	1090
10		Paris	Cedex 12	France	75557
11		Nantes	Cedex 1	France	44093
12		Bordeaux		France	33000
13		Dijon		France	21033
14		Marseille		France	13008
15		Paris		France	75015
16		Freiburg	Baden-Württemberg	Germany	79106
17		Heidelberg	Baden-Württemberg	Germany	69120
18		Tübingen	Baden-Württemberg	Germany	72076
19		München	Bayern	Germany	81675
20		Regensburg	Bayern	Germany	93053
21		Darmstadt	Hessen	Germany	64297
22		Frankfurt	Hessen	Germany	60596
23		Marburg	Hessen	Germany	35037
24		Göttingen	Niedersachsen	Germany	37075
25		Aachen	Nordrhein-Westfalen	Germany	52074
26		Bonn	Nordrhein-Westfalen	Germany	53105
27		Essen	Nordrhein-Westfalen	Germany	45122
28		Köln	Nordrhein-Westfalen	Germany	50924
29		Münster	Nordrhein-Westfalen	Germany	48145
30		Ludwigshafen	Rheinland-Pfalz	Germany	67063
31		Mainz	Rheinland-Pfalz	Germany	55131
32		Homburg	Saarland	Germany	66421
33		Chemnitz	Sachsen	Germany	09116
34		Dresden	Sachsen	Germany	01307
35		Dresden	Sachsen	Germany	06067
36		Leipzig	Sachsen	Germany	04103
37		Kiel	Schleswig-Holstein	Germany	24105
38		Lübeck	Schleswig-Holstein	Germany	23538
39		Berlin		Germany	13353
40		Hamburg		Germany	20251
41		Budapest		Hungary	1089
42		Budapest		Hungary	1106
43		Budapest		Hungary	1133
44		Debrecen		Hungary	4032
45		Veszprem		Hungary	8200
46		Zalaegerszeg		Hungary	H-8900
47		Ancona		Italy	60126
48		Bari		Italy	70124
49		Catania		Italy	95123
50		Firenze		Italy	50134
51		Milano		Italy	20122
52		Milano		Italy	20132
53		Milano		Italy	20157
54		Padova		Italy	35128
55		Roma		Italy	00133
56		Roma		Italy	00198
57		Torino		Italy	10122
58		Nagoya	Aichi	Japan	466-8560
59		Nagoya	Aichi	Japan	467-8602
60		Urayasu	Chiba	Japan	279-0021
61		Suita	Osaka	Japan	565-0871
62		Chiyoda-ku	Tokyo	Japan	101-8309
63		Kyoto		Japan	606-8507
64		Seongnam-si	Gyeonggido	Korea, Republic of	463-707
65		Incheon		Korea, Republic of	405-760
66		Seoul		Korea, Republic of	110 744
67		Seoul		Korea, Republic of	137-701
68		Seoul		Korea, Republic of	138-736
69		Seoul		Korea, Republic of
70		Riga		Latvia	1002
71		Riga		Latvia	1050
72		Singapore		Singapore	119074
73		Singapore		Singapore	168751

Sponsors and Collaborators

• Bayer
• Regeneron Pharmaceuticals

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01012973
• Other Study ID Numbers: 14130; 2009-010973-19
• First Posted: Nov 13, 2009
• Last Update Posted: Nov 2, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Bayer: Macular Edema; Central Retinal Vein Occlusion; CRVO; VEGF Trap-Eye; best-corrected visual acuity
• Additional relevant MeSH terms: Retinal Vein Occlusion; Aflibercept

Study Results

Participant Flow

Arm/Group Title	Aflibercept Injection First, Then Aflibercept Injection	Sham Treatment First, Then Aflibercept Injection
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Period Title: Overall Study
STARTED	106	71
Participants Received Treatment	104	68
Fulfilled Requirements of FAS Population	103	68
Completed Week 24, From FAS	97	57
Completed Week 52, From FAS	91	52
COMPLETED	90	52
NOT COMPLETED	16	19

Baseline Characteristics

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment	Total
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.	Total of all reporting groups
Overall Participants	104	68	172
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.0 (12.3)	63.8 (13.3)	61.5 (12.8)
Sex: Female, Male (Count of Participants)
Female	45 43.3%	31 45.6%	76 44.2%
Male	59 56.7%	37 54.4%	96 55.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 3.8%	1 1.5%	5 2.9%
Not Hispanic or Latino	100 96.2%	66 97.1%	166 96.5%
Unknown or Not Reported	0 0%	1 1.5%	1 0.6%
Baseline Best Corrected Visual Acuity (BCVA) letter scores (Letters correctly read) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Letters correctly read]	53.5 (15.7)	50.9 (15.4)	52.5 (15.6)
Number of participants with baseline retinal perfusion (Number) [Number]
Perfused	90 86.5%	54 79.4%	144 83.7%
Nonperfused	7 6.7%	7 10.3%	14 8.1%
Indeterminate	7 6.7%	7 10.3%	14 8.1%
Baseline Retinal Thickness by Optical Coherence Tomography (OCT) (microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [microns]	682.78 (233.36)	638.66 (224.69)	665.34 (230.33)
Baseline intraocular pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	15.2 (2.8)	14.4 (2.7)	14.9 (2.8)
Number of participants with time since Central retinal vein occlusion (CRVO) diagnosis (Number) [Number]
>= 2 months	46 44.2%	33 48.5%	79 45.9%
< 2 months	56 53.8%	35 51.5%	91 52.9%
Missing	2 1.9%	0 0%	2 1.2%
Baseline National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) total score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	79.66 (13.06)	78.94 (14.00)	79.38 (13.40)
European questionnaire 5 dimensions (EQ-5D) total score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	0.87 (0.15)	0.86 (0.16)	0.87 (0.15)
Race (Number) [Number]
Asian	26 25%	15 22.1%	41 23.8%
White	75 72.1%	49 72.1%	124 72.1%
Unknown or Not Reported	3 2.9%	4 5.9%	7 4.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures
Description	Defined study baseline range of Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision * 100); Denominator = Number of participants analyzed.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	103	68
Number [Percentage of participants]	60.2 57.9%	22.1 32.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments	Null hypothesis of difference of Eylea minus Sham of 0 was tested. In the database close after Week 24, basis for primary efficacy evaluation, 56 Sham / 96 Eylea subjects were considered as week 24 completers.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	CMH adjusted difference
	Estimated Value	38.3
	Confidence Interval	(2-Sided) 95%; 24.4 to 52.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is calculated as Eylea minus Sham. A positive value shows Eylea showed a higher BCVA total score compared to Sham.

2. Secondary Outcome

Title	Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF)
Description	Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. However, because this was assessed at the screening visit, subjects may have had a higher BCVA recorded at the baseline visit and would not have been excluded from the study.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	103	68
Mean (Standard Deviation) [Letters correctly read]	71.6 (17.1)	54.3 (20.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments	Null hypothesis was equality in change from baseline to Week 24 in BCVA total letter score between Eylea and Sham. If primary efficacy was successful, secondary efficacy endpoints were tested in a pre-specified fixed sequence testing procedure. Change in BCVA letter score was to be tested first in this sequence.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	As primary efficacy evaluation was significant, and this p-value was below significance level of two-sided <.05, the fixed sequence testing did continue with next secondary endpoint.
	Method	ANOVA
	Comments	ANOVA, adjusting for region and baseline BCVA category as fixed factors.
Method of Estimation	Estimation Parameter	Difference in Least square means
	Estimated Value	14.7
	Confidence Interval	(2-Sided) 95%; 10.8 to 18.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference is calculated as Eylea minus Sham. A positive value indicates Eylea showed a higher change in BCVA total score until week 24 compared to Sham.

3. Secondary Outcome

Title	Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	103	67
Mean (Standard Deviation) [microns]	-448.58 (256.02)	-169.27 (224.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments	Null hypothesis was equality in change from baseline to Week 24 in central retinal thickness between Eylea and Sham. If primary efficacy was successful, secondary efficacy end points were to be tested in a pre-specified fixed sequence testing procedure. Change in central retinal thickness was to be tested at second place in this sequence.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	As fixed sequence testing did reject nullhypothesis of change from baseline in BCVA until week 24, and this p-value was below significance level of two-sided <.05, the fixed sequence testing did continue with next secondary endpoint.
	Method	ANCOVA
	Comments	ANCOVA, stratified by region and baseline BCVA category, baseline central retinal thickness added as covariate.
Method of Estimation	Estimation Parameter	Difference in Least square (LS) means
	Estimated Value	-239.42
	Confidence Interval	(2-Sided) 95%; -286.31 to -192.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference is calculated as Eylea minus Sham. A negative value indicates Eylea showed a higher reduction in change in central retinal thickness until week 24 compared to Sham.

4. Secondary Outcome

Title	Percentage of Participants Who Developed Neovascularization During the First 24 Weeks
Description	Formation of blood vessels in the anterior segment, optic disc, or elsewhere in the fundus up to Week 24
Time Frame	From baseline until Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	103	68
Any neovascularization	2.9 2.8%	4.4 6.5%
Anterior segment neovascularization	1.9 1.8%	1.5 2.2%
Neovascularization of the optic disc (NVD)	0.0 0%	0.0 0%
Neovascularization elsewhere in the fundus (NVE)	1.0 1%	2.9 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments	Nullhypothesis of no difference in development of neovascularizations between Eylea and Sham group was tested. (Any neovascularization)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5947
	Comments	As fixed sequence testing did reject nullhypothesis of change from baseline in CRT until week 24, and this p-value was not below significance level of two-sided <.05, the fixed sequence testing did end with this evaluation.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochrane-Mantel-Haenszel test, stratified by region and baseline BCVA category.
Method of Estimation	Estimation Parameter	CMH adjusted Difference
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -7.4 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - 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 which are all scored from 0-100. To reach the overall composite score, each sub-scale score is averaged in order to give each sub-scale equal weight
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	96	65
Mean (Standard Deviation) [Scores on a scale]	7.46 (9.55)	3.55 (9.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	4.2
	Confidence Interval	(2-Sided) 95%; 1.7 to 6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	As the fixed sequence of secondary endpoints stopped with proportion of neovascularizations developed until week 24, 95% confidence interval is only of descriptive nature.

6. Secondary Outcome

Title	Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF
Description	EQ-5D is a quality of life questionnaire based on a scale from -0.594 (worst) to 1.00 (best).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF

Arm/Group Title	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)	Sham Treatment
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68.	Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68.
Measure Participants	95	64
Mean (Standard Deviation) [Scores on a scale]	0.029 (0.139)	-0.002 (0.195)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321), Sham Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.044
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	As the fixed sequence of secondary endpoints stopped with proportion of neovascularizations developed until week 24, 95% confidence interval is only of descriptive nature.

Adverse Events

Arm/Group Title	Aflibercept Injection (Until Week 20)		Sham Treatment (Until Week 20)		Aflibercept Injection (Until Week 48)		Sham Treatment (Until Week 48)		Aflibercept Injection Continued (Until Week 68)		Sham Treatment Then Aflibercept Injection (Until Week 68)
Arm/Group Description	Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20. Participants were observed until Week 24. Participants in the safety population were at risk.		Participants received sham treatment administered every 4 weeks from Day 1 through Week 20. Participants were observed until Week 24. Participants in the safety population were at risk.		Participants who continued the study drug until Week 24 received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Participants were observed from Week 24 until Week 52. Participants in the safety population that completed Week 24 were at risk.		Participants who continued the study drug until Week 24 received sham treatment administered every 4 weeks from Week 24 to Week 48. Participants were observed from Week 24 until Week 52. Participants in the safety population that completed Week 24 were at risk.		Participants on IAI who continued the study drug until Week 52, received 2 mg dose of IAI depending on the study retreatment criteria at Week 52, 60 and 68. Participants were observed starting from Week 52. Participants in the safety population that completed Week 52 were at risk.		Participants on sham treatment switched to IAI, received a 2 mg dose of IAI at Week 52 and depending on the study retreatment criteria at Week 60 and 68. Participants were observed starting from Week 52. Participants in the safety population that completed Week 52 were at risk.
All Cause Mortality
	Aflibercept Injection (Until Week 20)		Sham Treatment (Until Week 20)		Aflibercept Injection (Until Week 48)		Sham Treatment (Until Week 48)		Aflibercept Injection Continued (Until Week 68)		Sham Treatment Then Aflibercept Injection (Until Week 68)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aflibercept Injection (Until Week 20)		Sham Treatment (Until Week 20)		Aflibercept Injection (Until Week 48)		Sham Treatment (Until Week 48)		Aflibercept Injection Continued (Until Week 68)		Sham Treatment Then Aflibercept Injection (Until Week 68)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/104 (7.7%)		8/68 (11.8%)		14/97 (14.4%)		7/57 (12.3%)		4/91 (4.4%)		3/52 (5.8%)
Cardiac disorders
Aortic valve incompetence	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Cardiac failure	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Coronary artery stenosis	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Diastolic dysfunction	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Mitral valve incompetence	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Eye disorders
Blindness unilateral	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Glaucoma	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Iris neovascularisation	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Macular fibrosis	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Macular ischaemia	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Macular oedema	0/104 (0%)		2/68 (2.9%)		4/97 (4.1%)		0/57 (0%)		1/91 (1.1%)		0/52 (0%)
Retinal vein occlusion	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Visual acuity reduced	0/104 (0%)		1/68 (1.5%)		1/97 (1%)		0/57 (0%)		2/91 (2.2%)		0/52 (0%)
Vitreous detachment	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Vitreous haemorrhage	0/104 (0%)		1/68 (1.5%)		1/97 (1%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Gastrointestinal disorders
Diverticular perforation	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		1/91 (1.1%)		0/52 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Infections and infestations
Furuncle	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Gastroenteritis	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Pneumonia	0/104 (0%)		1/68 (1.5%)		1/97 (1%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Vestibular neuronitis	0/104 (0%)		0/68 (0%)		0/97 (0%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Injury, poisoning and procedural complications
Fall	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Femur fracture	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Hand fracture	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Humerus fracture	0/104 (0%)		1/68 (1.5%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Radius fracture	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Spinal compression fracture	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Spinal column stenosis	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		1/91 (1.1%)		0/52 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Oropharyngeal cancer stage unspecified	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Nervous system disorders
Paraesthesia	0/104 (0%)		0/68 (0%)		1/97 (1%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Syncope	0/104 (0%)		0/68 (0%)		1/97 (1%)		2/57 (3.5%)		0/91 (0%)		0/52 (0%)
Transient ischaemic attack	0/104 (0%)		0/68 (0%)		0/97 (0%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/104 (0%)		0/68 (0%)		0/97 (0%)		1/57 (1.8%)		0/91 (0%)		0/52 (0%)
Laryngeal granuloma	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Pulmonary hypertension	0/104 (0%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		1/52 (1.9%)
Surgical and medical procedures
Ischaemic heart disease prophylaxis	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Vascular disorders
Circulatory collapse	1/104 (1%)		0/68 (0%)		0/97 (0%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Aflibercept Injection (Until Week 20)		Sham Treatment (Until Week 20)		Aflibercept Injection (Until Week 48)		Sham Treatment (Until Week 48)		Aflibercept Injection Continued (Until Week 68)		Sham Treatment Then Aflibercept Injection (Until Week 68)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/104 (50%)		44/68 (64.7%)		66/97 (68%)		30/57 (52.6%)		38/91 (41.8%)		19/52 (36.5%)
Blood and lymphatic system disorders
Anaemia	1/104 (1%)		0/68 (0%)		0/97 (0%)		3/57 (5.3%)		0/91 (0%)		0/52 (0%)
Eye disorders
Conjunctival haemorrhage	10/104 (9.6%)		3/68 (4.4%)		3/97 (3.1%)		0/57 (0%)		9/91 (9.9%)		3/52 (5.8%)
Eye irritation	3/104 (2.9%)		7/68 (10.3%)		4/97 (4.1%)		1/57 (1.8%)		1/91 (1.1%)		2/52 (3.8%)
Eye pain	12/104 (11.5%)		3/68 (4.4%)		6/97 (6.2%)		2/57 (3.5%)		1/91 (1.1%)		0/52 (0%)
Foreign body sensation in eyes	6/104 (5.8%)		5/68 (7.4%)		2/97 (2.1%)		0/57 (0%)		1/91 (1.1%)		0/52 (0%)
Lacrimation increased	3/104 (2.9%)		4/68 (5.9%)		3/97 (3.1%)		4/57 (7%)		1/91 (1.1%)		2/52 (3.8%)
Macular fibrosis	1/104 (1%)		1/68 (1.5%)		5/97 (5.2%)		4/57 (7%)		0/91 (0%)		3/52 (5.8%)
Macular ischaemia	7/104 (6.7%)		5/68 (7.4%)		3/97 (3.1%)		1/57 (1.8%)		0/91 (0%)		1/52 (1.9%)
Macular oedema	2/104 (1.9%)		9/68 (13.2%)		30/97 (30.9%)		7/57 (12.3%)		17/91 (18.7%)		2/52 (3.8%)
Ocular hyperaemia	5/104 (4.8%)		4/68 (5.9%)		2/97 (2.1%)		1/57 (1.8%)		4/91 (4.4%)		1/52 (1.9%)
Optic disc vascular disorder	5/104 (4.8%)		3/68 (4.4%)		3/97 (3.1%)		3/57 (5.3%)		0/91 (0%)		0/52 (0%)
Retinal exudates	8/104 (7.7%)		5/68 (7.4%)		4/97 (4.1%)		3/57 (5.3%)		0/91 (0%)		0/52 (0%)
Retinal haemorrhage	4/104 (3.8%)		6/68 (8.8%)		11/97 (11.3%)		5/57 (8.8%)		5/91 (5.5%)		2/52 (3.8%)
Retinal vascular disorder	6/104 (5.8%)		7/68 (10.3%)		10/97 (10.3%)		2/57 (3.5%)		0/91 (0%)		2/52 (3.8%)
Visual acuity reduced	2/104 (1.9%)		7/68 (10.3%)		10/97 (10.3%)		1/57 (1.8%)		7/91 (7.7%)		1/52 (1.9%)
Vitreous detachment	2/104 (1.9%)		1/68 (1.5%)		7/97 (7.2%)		0/57 (0%)		0/91 (0%)		0/52 (0%)
Vitreous floaters	6/104 (5.8%)		0/68 (0%)		1/97 (1%)		1/57 (1.8%)		1/91 (1.1%)		1/52 (1.9%)
Gastrointestinal disorders
Nausea	0/104 (0%)		1/68 (1.5%)		0/97 (0%)		3/57 (5.3%)		0/91 (0%)		0/52 (0%)
Infections and infestations
Influenza	2/104 (1.9%)		0/68 (0%)		5/97 (5.2%)		1/57 (1.8%)		1/91 (1.1%)		1/52 (1.9%)
Nasopharyngitis	8/104 (7.7%)		6/68 (8.8%)		10/97 (10.3%)		11/57 (19.3%)		4/91 (4.4%)		2/52 (3.8%)
Investigations
Intraocular pressure increased	9/104 (8.7%)		4/68 (5.9%)		14/97 (14.4%)		2/57 (3.5%)		2/91 (2.2%)		1/52 (1.9%)
Visual acuity tests abnormal	0/104 (0%)		1/68 (1.5%)		5/97 (5.2%)		0/57 (0%)		1/91 (1.1%)		0/52 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/104 (1%)		5/68 (7.4%)		2/97 (2.1%)		1/57 (1.8%)		2/91 (2.2%)		0/52 (0%)
Nervous system disorders
Headache	7/104 (6.7%)		4/68 (5.9%)		4/97 (4.1%)		1/57 (1.8%)		1/91 (1.1%)		1/52 (1.9%)
Vascular disorders
Hypertension	4/104 (3.8%)		3/68 (4.4%)		4/97 (4.1%)		4/57 (7%)		3/91 (3.3%)		2/52 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Publishing of result communication only after Bayer´s written approval. Manuscript to Bayer sixty days before public release. If no written Bayer comment within 60 days consider approval given. If multi-site study, principal investigator (PI) not do independently publish results before publication of the multi-site paper, but PI not restricted from 24 months from study to completion onwards.