AQUA: Investigation of the Change of Vision-related Quality of Life in Subjects Treated With Aflibercept According to EU Label for DME.

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02581995
• Collaborator: (none)
• Enrollment: 560
• Locations: 76
• Arm: 1
• Actual Duration (Months): 20.7
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To evaluate the change in quality of life (NEI VFQ 25) in subjects with DME during the first year of treatment with aflibercept according to the EU Label.

Condition or Disease	Intervention/Treatment	Phase
Macular Edema	Drug: Eylea (Aflibercept, VEGF Trap-Eye, BAY86-5321)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 560 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label Phase-4 Study to Examine the Change of Vision-related Quality of Life in Subjects With Diabetic Macular Edema (DME) During Treatment With Intravitreal Injections of 2 mg Aflibercept According to EU Label for the First Year of Treatment
• Actual Study Start Date: Nov 19, 2015
• Actual Primary Completion Date: Aug 9, 2017
• Actual Study Completion Date: Aug 9, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 / Quality of Life Aflibercept treatment in subjects with diabetic macular edema (DME)	Drug: Eylea (Aflibercept, VEGF Trap-Eye, BAY86-5321); 2 mg aflibercept administered every 8 weeks following 5 initial monthly doses Intravitreal (IVT) injection

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 52 in NEI VFQ-25 Total Score [Baseline, Week 52]

   National eye institute 25-item visual function questionnaire (NEI VFQ-25) is a condition-specific measure which was designed to capture the specific impact of vision loss on health-related quality of life (HRQoL). The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. In this format scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score.

Secondary Outcome Measures

1. Change From Baseline to Week 52 in the NEI VFQ 25 Near Activities Subscale [Baseline, Week 52]

   NEI VFQ-25 is a condition-specific measure which was designed to capture the specific impact of vision loss on HRQoL. The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". Items within each sub-scale are averaged together to create the 12 sub-scale Scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Sub-scales with at least one item answered can be used to generate a sub-scale score. Hence, scores represent the average for all items in the subscale that the respondent answered.The NEI VFQ-25 near activities subscale was scored from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf.

2. Change From Baseline to Week 52 in the NEI VFQ 25 Distant Activities Subscale [Baseline, Week 52]

   NEI VFQ-25 is a condition-specific measure which was designed to capture the specific impact of vision loss on HRQoL. The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". Items within each sub-scale are averaged together to create the 12 sub-scale Scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Sub-scales with at least one item answered can be used to generate a sub-scale score. Hence, scores represent the average for all items in the subscale that the respondent answered. The NEI VFQ-25 distant activities subscale was scored from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. Distant activities are defined as activities requiring distance vision, such as recognizing faces or reading street signs.

3. Change From Baseline to Week 52 in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score]) [Baseline, Week 52]

   Visual function was assessed using the ETDRS protocol (Early Treatment Diabetic Retinopathy Study Research Group 1985) starting at 4 meters. The values might range from 0 to 100. A higher score represents better functioning.

4. Change From Baseline to Week 52 in Central Retinal Thickness (CRT) Measured by Optical Coherence Tomography (OCT) [Baseline, Week 52]

   Retinal and lesion characteristics were evaluated using spectral domain optical coherence tomography (OCT). For all visits where the OCT procedure was scheduled, images were captured and read by the investigator. All OCTs were electronically archived at the study sites as part of the source documentation.

5. Proportion of Participants Progressing to Greater or Equal to (>=) 61 on the ETDRS Diabetic Retinopathy Severity Scale (DRSS) as Assessed by Fundus Photography (FP) [Baseline, Week 52]

   The ETDRS DRSS was assessed by FP according to the following scale for both eyes. The following severities are possible. 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85.

Other Outcome Measures

1. Change From Baseline in Pre-injection Intraocular Pressure for Study Eye Every 4 Weeks [Baseline, Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52]

   Intraocular pressure (IOP) was measured using applanation tonometry Goldmann, Tonopen or approved alternative). The same method of intraocular pressure measurement was used in each participant throughout the study. For the measurement of intraocular pressure, a local anesthetic combined with fluorescein was applied topically to the eye being tested (example: one drop of oxybuprocain plus fluorescein). In the below table, pre-injection intraocular pressure for study eye was reported.

2. Change From Baseline in Systolic Blood Pressure at Week 52 [Baseline, Week 52]

   Systolic blood pressure was measured in a consistent and standardized way according to locally established practice.

3. Change From Baseline in Diastolic Blood Pressure at Week 52 [Baseline, Week 52]

   Diastolic blood pressure was measured in a consistent and standardized way according to locally established practice.

4. Change From Baseline in Heart Rate at Week 52 [Baseline, Week 52]

   Heart rate was measured in a consistent and standardized way according to locally established practice.

5. Change From Baseline in Body Temperature at Week 52 [Baseline, Week 52]

   Temperature was measured in a consistent and standardized way according to locally established practice.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Type 1 or 2 diabetes mellitus

• Diagnosis of DME secondary to diabetes mellitus involving the center of the macula (defined as the area of the center subfield on OCT) in the study eye

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

• BCVA in the study eye of ETDRS letter score 73 to 24 (This corresponds to a Snellen equivalent of approximately 20/40 to 20/320.)

Exclusion Criteria:

• Pregnancy and lactation

• Mismatch with inclusion criteria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Graz	Steiermark	Austria	8036
2		Wien		Austria	1090
3		Wien		Austria	1140
4		Halifax	Nova Scotia	Canada	B3H 2Y9
5		London	Ontario	Canada	N6A 4V2
6		Mississauga	Ontario	Canada	L4W 1W9
7		Ottawa	Ontario	Canada	K1H 8L6
8		Toronto	Ontario	Canada	M3C 0G9
9		Montreal	Quebec	Canada	H4P 2S4
10		Sherbrooke	Quebec	Canada	J1G 2V4
11		Hradec Kralove		Czechia	500 05
12		Praha 10		Czechia	100 34
13		Usti nad Labem		Czechia	401 13
14		Creteil Cedex		France	94010
15		Marseille		France	13285
16		Darmstadt	Hessen	Germany	64276
17		Frankfurt	Hessen	Germany	60596
18		Marburg	Hessen	Germany	35043
19		Göttingen	Niedersachsen	Germany	37099
20		Bonn	Nordrhein-Westfalen	Germany	53105
21		Köln	Nordrhein-Westfalen	Germany	50937
22		Ludwigshafen	Rheinland-Pfalz	Germany	67063
23		Mainz	Rheinland-Pfalz	Germany	55131
24		Dresden	Sachsen	Germany	01067
25		Dresden	Sachsen	Germany	01307
26		Leipzig	Sachsen	Germany	04103
27		Budapest		Hungary	1083
28		Budapest		Hungary	1106
29		Budapest		Hungary	1133
30		Debrecen		Hungary	4032
31		Pecs		Hungary	7621
32		Roma	Lazio	Italy	00133
33		Genova	Liguria	Italy	16132
34		Milano	Lombardia	Italy	20122
35		Milano	Lombardia	Italy	20132
36		Torino	Piemonte	Italy	10122
37		Cagliari	Sardegna	Italy	09124
38		Sassari	Sardegna	Italy	07100
39		Firenze	Toscana	Italy	50134
40		Padova	Veneto	Italy	35128
41		Kaunas		Lithuania	LT-50009
42		Vilnius		Lithuania	LT-08661
43		Bydgoszcz		Poland	85-631
44		Gdansk		Poland	80-809
45		Katowice		Poland	40-594
46		Krakow		Poland	31-501
47		Lodz		Poland	91-134
48		Lublin		Poland	20-079
49		Poznan		Poland	61-285
50		Warszawa		Poland	01-013
51		Warszawa		Poland	04-141
52		Coimbra		Portugal	3000-548
53		Leiria		Portugal	2410-197
54		Lisboa		Portugal	1649-035
55		Porto		Portugal	4200-319
56		Vila Franca de Xira		Portugal	2600-178
57		Bratislava		Slovakia	826 06
58		Bratislava		Slovakia	85107
59		Nitra		Slovakia	949 01
60		Zilina		Slovakia	01207
61		Zvolen		Slovakia	960 01
62		L'Hospitalet de Llobregat	Barcelona	Spain	08907
63		San Cugat Del Vallès	Barcelona	Spain	08190
64		Albacete		Spain	02006
65		Barcelona		Spain	08035
66		Barcelona		Spain	08036
67		Valencia		Spain	46014
68		Bern		Switzerland
69		Genève		Switzerland	1204
70		Southampton	Hampshire	United Kingdom	SO16 6YD
71		Camberley	Surrey	United Kingdom	GU16 7UJ
72		Guildford	Surrey	United Kingdom	GU2 7XX
73		Newcastle Upon Tyne	Tyne And Wear	United Kingdom	NE1 4LP
74		Sunderland	Tyne And Wear	United Kingdom	SR2 9HP
75		Leeds	West Yorkshire	United Kingdom	LS9 7TF
76		London		United Kingdom	EC1V 2PD

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

• Statistical Analysis Plan - May 4, 2017
• Study Protocol - Sep 7, 2015

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02581995
• Other Study ID Numbers: 17850; 2014-005119-17
• First Posted: Oct 21, 2015
• Last Update Posted: Oct 10, 2018
• Last Verified: Sep 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Bayer: Diabetic macular edema; Intravitreal injection
• Additional relevant MeSH terms: Macular Edema; Edema; Aflibercept

Study Results

Participant Flow

Recruitment Details	Study was conducted at multiple study centers in 14 countries, between 19 November 2015 (first participant first visit) and 09 August 2017 (last participant last visit).
Pre-assignment Detail	Overall, 676 participants were screened. Of them, 116 participants did not complete screening: 100 failed screening; 8 withdrew, 1 had an adverse event, 1 was lost to follow-up and 6 were not assigned to treatment for other reasons. A total of 560 participants were assigned to treatment and 31 participants discontinued the study prematurely.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Period Title: Overall Study
STARTED	560
Treated	560
COMPLETED	529
NOT COMPLETED	31

Baseline Characteristics

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Overall Participants	560
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.3 (9.3)
Sex: Female, Male (Count of Participants)
Female	224 40%
Male	336 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 0.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 0.5%
White	519 92.7%
More than one race	0 0%
Unknown or Not Reported	34 6.1%
Central Retinal Thickness (CRT) (microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [microns]	465.08 (136.75)
Best Corrected Visual Acuity (BCVA) (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	61.5 (11.0)
NEI VFQ-25 total score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	70.224 (19.221)
NEI VFQ-25 near activities subscale (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	62.967 (23.479)
NEI VFQ-25 distant activities subscale (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	71.964 (23.973)
Number of Participants with Diabetic Retinopathy Severity Score (DRSS) (Count of Participants)
10 - DR absent	0 0%
15 - DR questionable	2 0.4%
35 - Mild NPDR	144 25.7%
43 - Moderate NPDR	184 32.9%
47 - Moderately severe NPDR	151 27%
53 - Severe NPDR	48 8.6%
61 - Mild PDR	8 1.4%
65 - Moderate PDR	8 1.4%
71 - High-risk PDR	2 0.4%
90 - Cannot grade	6 1.1%
Pre-injection Intraocular Pressure (millimeter of mercury (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	16.2 (3.0)
Systolic Blood Pressure (millimeter of mercury (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	138.1 (13.6)
Diastolic Blood Pressure (millimeter of mercury (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	77.7 (9.4)
Heart Rate (beats per minute (beats/min)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute (beats/min)]	75.1 (10.1)
Body Temperature (celsius) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [celsius]	36.37 (0.38)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 52 in NEI VFQ-25 Total Score
Description	National eye institute 25-item visual function questionnaire (NEI VFQ-25) is a condition-specific measure which was designed to capture the specific impact of vision loss on health-related quality of life (HRQoL). The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. In this format scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least one injection of study drug and completed the baseline and at least one post-baseline NEI VFQ-25 questionnaire.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Mean (95% Confidence Interval) [score on a scale]	6.106

2. Secondary Outcome

Title	Change From Baseline to Week 52 in the NEI VFQ 25 Near Activities Subscale
Description	NEI VFQ-25 is a condition-specific measure which was designed to capture the specific impact of vision loss on HRQoL. The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". Items within each sub-scale are averaged together to create the 12 sub-scale Scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Sub-scales with at least one item answered can be used to generate a sub-scale score. Hence, scores represent the average for all items in the subscale that the respondent answered.The NEI VFQ-25 near activities subscale was scored from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. 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, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least one injection of study drug and completed the baseline and at least one post-baseline NEI VFQ-25 questionnaire.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Mean (95% Confidence Interval) [score on a scale]	11.370

3. Secondary Outcome

Title	Change From Baseline to Week 52 in the NEI VFQ 25 Distant Activities Subscale
Description	NEI VFQ-25 is a condition-specific measure which was designed to capture the specific impact of vision loss on HRQoL. The calculation for NEI VFQ-25 sub-scale scores and total score was performed according to the "NEI VFQ-25 Scoring Algorithm - August 2000". Items within each sub-scale are averaged together to create the 12 sub-scale Scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Sub-scales with at least one item answered can be used to generate a sub-scale score. Hence, scores represent the average for all items in the subscale that the respondent answered. The NEI VFQ-25 distant activities subscale was scored from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. Distant activities are defined as activities requiring distance vision, such as recognizing faces or reading street signs.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least one injection of study drug and completed the baseline and at least one post-baseline NEI VFQ-25 questionnaire.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Mean (95% Confidence Interval) [score on a scale]	7.331

4. Secondary Outcome

Title	Change From Baseline to Week 52 in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score])
Description	Visual function was assessed using the ETDRS protocol (Early Treatment Diabetic Retinopathy Study Research Group 1985) starting at 4 meters. The values might range from 0 to 100. A higher score represents better functioning.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least one injection of study drug and completed the baseline and at least one post-baseline NEI VFQ-25 questionnaire.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Mean (95% Confidence Interval) [score on a scale]	10.0

5. Secondary Outcome

Title	Change From Baseline to Week 52 in Central Retinal Thickness (CRT) Measured by Optical Coherence Tomography (OCT)
Description	Retinal and lesion characteristics were evaluated using spectral domain optical coherence tomography (OCT). For all visits where the OCT procedure was scheduled, images were captured and read by the investigator. All OCTs were electronically archived at the study sites as part of the source documentation.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least one injection of study drug and completed the baseline and at least one post-baseline NEI VFQ-25 questionnaire. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Mean (95% Confidence Interval) [microns]	-175.38

6. Secondary Outcome

Title	Proportion of Participants Progressing to Greater or Equal to (>=) 61 on the ETDRS Diabetic Retinopathy Severity Scale (DRSS) as Assessed by Fundus Photography (FP)
Description	The ETDRS DRSS was assessed by FP according to the following scale for both eyes. The following severities are possible. 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Subjects in the FAS with gradable baseline and Week 52 FP and a DRSS of less than (<) 61 at baseline. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	553
Number [proportion of participants]	0.4 0.1%

7. Other Pre-specified Outcome

Title	Change From Baseline in Pre-injection Intraocular Pressure for Study Eye Every 4 Weeks
Description	Intraocular pressure (IOP) was measured using applanation tonometry Goldmann, Tonopen or approved alternative). The same method of intraocular pressure measurement was used in each participant throughout the study. For the measurement of intraocular pressure, a local anesthetic combined with fluorescein was applied topically to the eye being tested (example: one drop of oxybuprocain plus fluorescein). In the below table, pre-injection intraocular pressure for study eye was reported.
Time Frame	Baseline, Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52

Outcome Measure Data

Analysis Population Description

SAF included all participants who received at least 1 injection of study drug. Participants who were evaluable for this measure at given time points for the arm were included in the categories.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	560
Change at Week 4	-0.4 (2.9)
Change at Week 8	-0.3 (2.9)
Change at Week 12	-0.5 (2.9)
Change at Week 16	-0.3 (2.9)
Change at Week 24	-0.2 (3.0)
Change at Week 32	-0.1 (3.0)
Change at Week 40	0.0 (3.0)
Change at Week 48	0.0 (3.0)
Change at Week 52	0.1 (3.1)

8. Other Pre-specified Outcome

Title	Change From Baseline in Systolic Blood Pressure at Week 52
Description	Systolic blood pressure was measured in a consistent and standardized way according to locally established practice.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

SAF included all participants who received at least 1 injection of study drug. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	560
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	-0.1 (15.1)

9. Other Pre-specified Outcome

Title	Change From Baseline in Diastolic Blood Pressure at Week 52
Description	Diastolic blood pressure was measured in a consistent and standardized way according to locally established practice.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

SAF included all participants who received at least 1 injection of study drug. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	560
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	-0.3 (9.9)

10. Other Pre-specified Outcome

Title	Change From Baseline in Heart Rate at Week 52
Description	Heart rate was measured in a consistent and standardized way according to locally established practice.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

SAF included all participants who received at least 1 injection of study drug. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	560
Mean (Standard Deviation) [beats per minute (beats/min)]	-1.0 (9.5)

11. Other Pre-specified Outcome

Title	Change From Baseline in Body Temperature at Week 52
Description	Temperature was measured in a consistent and standardized way according to locally established practice.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

SAF included all participants who received at least 1 injection of study drug. Participants who were evaluable for this measure at given time point for the arm were included in the category.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
Measure Participants	560
Mean (Standard Deviation) [celsius]	-0.04 (0.41)

Adverse Events

Time Frame	From start of study treatment up to 30 days after the last injection of study treatment, up to week 52
Arm/Group Title	Aflibercept
Arm/Group Description	Participants were treated according to the EU-PI for treatment of DME for the first year of treatment and received 1 dose of 2 mg aflibercept injected IVT every 4 weeks for 5 consecutive doses, followed by dosing every 8 weeks thereafter until the end of the 52 week treatment period.
All Cause Mortality
	Aflibercept
	Affected / at Risk (%)	# Events
Total	5/560 (0.9%)
Serious Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	66/560 (11.8%)
Cardiac disorders
Atrioventricular block	1/560 (0.2%)	1
Bundle branch block right	1/560 (0.2%)	1
Cardiac failure	1/560 (0.2%)	1
Cardiac failure acute	2/560 (0.4%)	3
Cardiac failure chronic	1/560 (0.2%)	1
Cardiac failure congestive	1/560 (0.2%)	1
Cardio-respiratory arrest	1/560 (0.2%)	1
Cardiopulmonary failure	1/560 (0.2%)	1
Cardiovascular insufficiency	1/560 (0.2%)	1
Mitral valve incompetence	1/560 (0.2%)	1
Myocardial infarction	2/560 (0.4%)	2
Eye disorders
Anterior chamber inflammation	1/560 (0.2%)	1
Cataract subcapsular	1/560 (0.2%)	1
Posterior capsule opacification	2/560 (0.4%)	2
Vitreous haemorrhage	1/560 (0.2%)	1
Vitritis	2/560 (0.4%)	2
Gastrointestinal disorders
Abdominal hernia	1/560 (0.2%)	1
Pancreatitis acute	1/560 (0.2%)	1
Peptic ulcer haemorrhage	1/560 (0.2%)	1
Umbilical hernia	1/560 (0.2%)	1
Hepatobiliary disorders
Cholelithiasis	1/560 (0.2%)	1
Infections and infestations
Anal abscess	1/560 (0.2%)	1
Boutonneuse fever	1/560 (0.2%)	1
Cellulitis	2/560 (0.4%)	2
Diabetic foot infection	2/560 (0.4%)	2
Endophthalmitis	3/560 (0.5%)	3
Erysipelas	1/560 (0.2%)	1
Osteomyelitis	1/560 (0.2%)	1
Parotitis	1/560 (0.2%)	1
Pneumonia	6/560 (1.1%)	6
Pyelonephritis chronic	1/560 (0.2%)	1
Septic shock	1/560 (0.2%)	1
Injury, poisoning and procedural complications
Ankle fracture	1/560 (0.2%)	1
Carbon monoxide poisoning	1/560 (0.2%)	1
Femoral neck fracture	1/560 (0.2%)	1
Fracture	1/560 (0.2%)	1
Humerus fracture	1/560 (0.2%)	1
Inflammation of wound	1/560 (0.2%)	1
Rib fracture	2/560 (0.4%)	2
Investigations
Echocardiogram abnormal	1/560 (0.2%)	1
Influenza A virus test positive	1/560 (0.2%)	1
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/560 (0.2%)	1
Diabetic metabolic decompensation	1/560 (0.2%)	1
Hyperkalaemia	1/560 (0.2%)	1
Type 1 diabetes mellitus	1/560 (0.2%)	1
Type 2 diabetes mellitus	2/560 (0.4%)	2
Musculoskeletal and connective tissue disorders
Pain in extremity	1/560 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	1/560 (0.2%)	1
Metastases to lymph nodes	1/560 (0.2%)	1
Metastases to peritoneum	1/560 (0.2%)	1
Metastatic malignant melanoma	1/560 (0.2%)	1
Small cell lung cancer	1/560 (0.2%)	1
Nervous system disorders
Cerebrovascular accident	3/560 (0.5%)	3
Lacunar stroke	1/560 (0.2%)	1
Transient ischaemic attack	1/560 (0.2%)	1
Vascular encephalopathy	2/560 (0.4%)	2
Psychiatric disorders
Depression	2/560 (0.4%)	2
Major depression	1/560 (0.2%)	1
Suicide attempt	1/560 (0.2%)	1
Renal and urinary disorders
Chronic kidney disease	1/560 (0.2%)	1
Diabetic nephropathy	2/560 (0.4%)	2
Reproductive system and breast disorders
Prostatitis	1/560 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/560 (0.2%)	1
Pulmonary embolism	1/560 (0.2%)	1
Surgical and medical procedures
Umbilical hernia repair	1/560 (0.2%)	1
Vitrectomy	1/560 (0.2%)	1
Vascular disorders
Arteriosclerosis	1/560 (0.2%)	1
Hypertensive crisis	1/560 (0.2%)	1
Peripheral arterial occlusive disease	2/560 (0.4%)	2
Peripheral vascular disorder	1/560 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	0/560 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Center provides publication/presentation related to the Study Drug/Results 60 days prior to due date submission/presentation allowing Bayer review. Center receives notification within 45 days, Center reminds Bayer of Publication´s due date. Expected comments are within 60 days, if not Center to publish. Multi-center´s Results publication coordinates through Bayer Center publishes their Results provided overall results haven't been published within 18 months from Study completion for compliance.