VISTA DME: Study of Intravitreal Aflibercept Injection (IAI; EYLEA®; BAY86-5321) in Patients With Diabetic Macular Edema

• Sponsor: Regeneron Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01363440
• Collaborator: Bayer (Industry)
• Enrollment: 466
• Locations: 51
• Arms: 3
• Duration (Months): 42.1
• Patients Per Site: 9.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy of Intravitreal Aflibercept Injection (IAI; EYLEA®; BAY86-5321) on the best corrected visual acuity (BCVA) assessed by the early treatment diabetic retinopathy study (ETDRS) chart in patients with diabetic macular edema (DME) with central involvement.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Intravitreal Aflibercept Injection (IAI; EYLEA®; BAY86-5321); Procedure: Macular Laser Photocoagulation	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 466 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Masked, Randomized, Active-Controlled, Phase 3 Study of the Efficacy and Safety of Intravitreal Administration of VEGF Trap-Eye in Patients With Diabetic Macular Edema
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

   Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye were included; 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 and Week 52]

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 and Week 52]

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 and 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 and 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 and 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 and 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:

The following is an abbreviated list of inclusion criteria:

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

• 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:

The following is an abbreviated list of exclusion criteria:

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

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

• Previous treatment with anti-angiogenic drugs in the study eye (pegaptanib sodium, bevacizumab, ranibizumab, etc.) within 90 days of day 1

• Active proliferative diabetic retinopathy (PDR) in the study eye

• Uncontrolled diabetes mellitus

• 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		Phoenix	Arizona	United States
2		Tucson	Arizona	United States
3		Arcadia	California	United States
4		Beverly Hills	California	United States
5		La Jolla	California	United States
6		Mountain View	California	United States
7		Oakland	California	United States
8		Palm Desert	California	United States
9		Sacramento	California	United States
10		San Francisco	California	United States
11		Santa Barbara	California	United States
12		Torrance	California	United States
13		Colorado Springs	Colorado	United States
14		Golden	Colorado	United States
15		New London	Connecticut	United States
16		Fort Lauderdale	Florida	United States
17		Fort Myers	Florida	United States
18		Miami	Florida	United States
19		Orlando	Florida	United States
20		Winter Haven	Florida	United States
21		Augusta	Georgia	United States
22		Aiea	Hawaii	United States
23		Wichita	Kansas	United States
24		Portland	Maine	United States
25		Baltimore	Maryland	United States
26		Boston	Massachusetts	United States
27		Missoula	Montana	United States
28		Las Vegas	Nevada	United States
29		New Brunswick	New Jersey	United States
30		Northfield	New Jersey	United States
31		Teaneck	New Jersey	United States
32		Lynbrook	New York	United States
33		Orchard Park	New York	United States
34		Rochester	New York	United States
35		Asheville	North Carolina	United States
36		Charlotte	North Carolina	United States
37		Raleigh	North Carolina	United States
38		Portland	Oregon	United States
39		Kingston	Pennsylvania	United States
40		Pittsburgh	Pennsylvania	United States
41		Florence	South Carolina	United States
42		West Columbia	South Carolina	United States
43		Rapid City	South Dakota	United States
44		Nashville	Tennessee	United States
45		Abilene	Texas	United States
46		Austin	Texas	United States
47		Harlingen	Texas	United States
48		Houston	Texas	United States
49		San Antonio (2 locations)	Texas	United States
50		The Woodlands	Texas	United States
51		Salt Lake City	Utah	United States

Sponsors and Collaborators

• Regeneron Pharmaceuticals
• Bayer

Investigators

• Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01363440
• Other Study ID Numbers: VGFT-OD-1009
• First Posted: Jun 1, 2011
• Last Update Posted: May 30, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Regeneron Pharmaceuticals: Diabetic Macular Edema; Diabetic Retinopathy
• 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.
Pre-assignment Detail	Of 687 participants who were screened for inclusion in the study, 466 were enrolled (started) and 461 received treatment.

Arm/Group Title	Macular Laser Photocoagulation Treatment (Control)	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Period Title: Overall Study
STARTED	156	156	154
Participants Received Treatment	154	155	152
Completed Week 52	145	146	144
Completed Week 100	133	125	127
COMPLETED	133	125	127
NOT COMPLETED	23	31	27

Baseline Characteristics

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8	Total
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.	Total of all reporting groups
Overall Participants	154	155	152	461
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (8.65)	62 (11.16)	63.1 (9.36)	62.2 (9.7)
Sex: Female, Male (Count of Participants)
Female	69 44.8%	68 43.9%	73 48%	210 45.6%
Male	85 55.2%	87 56.1%	79 52%	251 54.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity (BCVA) 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. Participants with a BCVA ETDRS letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye were included; a higher score represents better functioning.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

The Primary efficacy endpoint was analyzed using the full analysis set (FAS). The FAS included all 'Participants received Treatment' and had a baseline and at least 1 post-baseline assessment of Best Corrected Visual Acuity (BCVA).

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Least Squares Mean (Standard Error) [letters correctly read]	.10 (1.03)	12.3 (.76)	10.6 (.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	12.19
	Confidence Interval	(2-Sided) 97.5%; 9.35 to 15.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	10.45
	Confidence Interval	(2-Sided) 97.5%; 7.73 to 13.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

All secondary efficacy endpoints were analyzed using the full analysis set (FAS). The FAS included all 'Participants received Treatment' and had a baseline and at least 1 post-baseline assessment of Best Corrected Visual Acuity (BCVA).

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Number [percentage of participants]	30 19.5%	100 64.5%	88 57.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	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	Mean Difference (Net)
	Estimated Value	45.9
	Confidence Interval	(2-Sided) 97.5%; 34.7 to 57.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	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	Mean Difference (Net)
	Estimated Value	38.8
	Confidence Interval	(2-Sided) 97.5%; 27.2 to 50.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Number [percentage of participants]	12 7.8%	64 41.3%	47 30.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	34.2
	Confidence Interval	(2-Sided) 97.5%; 24.1 to 44.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	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	Mean Difference (Net)
	Estimated Value	23.3
	Confidence Interval	(2-Sided) 97.5%; 13.5 to 33.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Number [percentage of participants]	22 14.3%	52 33.5%	44 28.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	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	Mean Difference (Net)
	Estimated Value	19.7
	Confidence Interval	(2-Sided) 97.5%; 9.0 to 30.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	14.9
	Confidence Interval	(2-Sided) 97.5%; 4.4 to 25.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Least Squares Mean (Standard Error) [microns]	-73.3 (12.09)	-184.1 (6.57)	-186.8 (6.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-110.8
	Confidence Interval	(2-Sided) 97.5%; -141.3 to -80.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-113.5
	Confidence Interval	(2-Sided) 97.5%; -144.2 to -82.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Least Squares Mean (Standard Error) [scores on a scale]	3.7 (1.55)	8.9 (1.58)	8.1 (1.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0168
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.19
	Confidence Interval	() 97.5%; 0.33 to 10.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0323
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.36
	Confidence Interval	(2-Sided) 97.5%; -0.21 to 8.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4	Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.	Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
Measure Participants	154	154	151
Least Squares Mean (Standard Error) [scores on a scale]	4.9 (1.44)	7.7 (1.57)	6.5 (1.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1702
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.86
	Confidence Interval	(2-Sided) 97.5%; -1.82 to 7.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Control, Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4067
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 97.5%; -2.83 to 6.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the first study drug injection until 30 days after the last study drug injection at the latest from week 0 to week 100; From the first study drug injection until 30 days after the last study drug injection at the latest from week 0 to week 148.
Arm/Group Title	Control (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 100)		Control (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 148)
Arm/Group Description	Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.		Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks.		Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.		Participants received macular laser treatment at baseline and as-needed at visits at which laser re-treatment criteria were met, but no more frequently than every 12 weeks.		Participants received 2mg Intravitreal aflibercept injection(IAI) every 4 weeks.		Participants received 2mg Intravitreal aflibercept injection (IAI) every 4 weeks for 5 visits followed by injections every 8 weeks.
All Cause Mortality
	Control (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 100)		Control (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 148)
	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
	Control (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 100)		Control (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 148)
	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	67/154 (43.5%)		67/155 (43.2%)		56/152 (36.8%)		84/154 (54.5%)		85/155 (54.8%)		75/152 (49.3%)
Blood and lymphatic system disorders
Anaemia	1/154 (0.6%)		9/155 (5.8%)		5/152 (3.3%)		2/154 (1.3%)		10/155 (6.5%)		6/152 (3.9%)
Coagulopathy	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Haemorrhagic anaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Microcytic anaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Nephrogenic anaemia	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Normochromic normocytic anaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Cardiac disorders
Acute coronary syndrome	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Acute myocardial infarction	3/154 (1.9%)		2/155 (1.3%)		2/152 (1.3%)		4/154 (2.6%)		2/155 (1.3%)		3/152 (2%)
Angina pectoris	1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)		1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)
Angina unstable	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		2/152 (1.3%)
Arteriosclerosis coronary artery	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Atrial fibrillation	0/154 (0%)		1/155 (0.6%)		3/152 (2%)		0/154 (0%)		2/155 (1.3%)		4/152 (2.6%)
Atrial flutter	0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Atrioventricular block complete	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Bradycardia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Cardiac arrest	2/154 (1.3%)		1/155 (0.6%)		1/152 (0.7%)		3/154 (1.9%)		2/155 (1.3%)		1/152 (0.7%)
Cardiac failure	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Cardiac failure acute	4/154 (2.6%)		1/155 (0.6%)		0/152 (0%)		4/154 (2.6%)		2/155 (1.3%)		1/152 (0.7%)
Cardiac failure chronic	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Cardiac failure congestive	5/154 (3.2%)		9/155 (5.8%)		5/152 (3.3%)		6/154 (3.9%)		11/155 (7.1%)		6/152 (3.9%)
Cor pulmonale chronic	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Coronary artery disease	2/154 (1.3%)		4/155 (2.6%)		2/152 (1.3%)		2/154 (1.3%)		5/155 (3.2%)		4/152 (2.6%)
Coronary artery occlusion	0/154 (0%)		0/155 (0%)		2/152 (1.3%)		0/154 (0%)		0/155 (0%)		2/152 (1.3%)
Coronary artery stenosis	3/154 (1.9%)		4/155 (2.6%)		5/152 (3.3%)		3/154 (1.9%)		4/155 (2.6%)		5/152 (3.3%)
Coronary ostial stenosis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ischaemic cardiomyopathy	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Mitral valve incompetence	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Myocardial infarction	3/154 (1.9%)		5/155 (3.2%)		3/152 (2%)		3/154 (1.9%)		4/155 (2.6%)		2/152 (1.3%)
Myocardial ischaemia	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Pericardial effusion	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Right ventricular failure	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Supraventricular tachycardia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		2/152 (1.3%)
Systolic dysfunction	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ventricular fibrillation	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Ventricular tachycardia	1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Ear and labyrinth disorders
Vertigo positional	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Eye disorders
Cataract	0/154 (0%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		1/152 (0.7%)
Cataract	1/154 (0.6%)		4/155 (2.6%)		0/152 (0%)		1/154 (0.6%)		4/155 (2.6%)		0/152 (0%)
Cataract subcapsular	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Cataract subcapsular	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Corneal epithelium defect	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Diabetic retinal oedema	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Diabetic retinal oedema	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Diabetic retinopathy	2/154 (1.3%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Diabetic retinopathy	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Hyphaema	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Intraocular pressure increased	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Iris neovascularisation	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Lens dislocation	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Macular ischaemia	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Punctate keratitis	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Punctate keratitis	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal aneurysm	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal artery occlusion	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal artery occlusion	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Retinal detachment	1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)		2/154 (1.3%)		3/155 (1.9%)		0/152 (0%)
Retinal detachment	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		3/155 (1.9%)		0/152 (0%)
Retinal haemorrhage	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Retinal haemorrhage	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal ischaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal ischaemia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal neovascularisation	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Retinal tear	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Retinal vascular disorder	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Retinal vein occlusion	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Visual acuity reduced	1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Visual acuity reduced	0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Vitreous haemorrhage	3/154 (1.9%)		2/155 (1.3%)		1/152 (0.7%)		3/154 (1.9%)		3/155 (1.9%)		2/152 (1.3%)
Vitreous haemorrhage	2/154 (1.3%)		7/155 (4.5%)		2/152 (1.3%)		3/154 (1.9%)		9/155 (5.8%)		4/152 (2.6%)
Vitreous haemorrhage	0/154 (0%)		0/155 (0%)		0/152 (0%)		3/154 (1.9%)		9/155 (5.8%)		4/152 (2.6%)
Vitreous opacities	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Gastrointestinal disorders
Abdominal hernia	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Colitis	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Colitis ischaemic	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Constipation	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Diabetic gastroparesis	2/154 (1.3%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Diarrhoea	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Diverticulum	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Gastric ulcer haemorrhage	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Gastrointestinal haemorrhage	2/154 (1.3%)		3/155 (1.9%)		1/152 (0.7%)		2/154 (1.3%)		4/155 (2.6%)		1/152 (0.7%)
Gastrooesophageal reflux disease	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		2/152 (1.3%)
Haematemesis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Hiatus hernia	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ileus	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Impaired gastric emptying	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Internal hernia	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Mallory-Weiss syndrome	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Nausea	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Oesophageal ulcer	1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Oesophagitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Pancreatitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)
Pancreatitis acute	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Retroperitoneal haemorrhage	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Small intestinal obstruction	2/154 (1.3%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Volvulus of small bowel	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
General disorders
Asthenia	0/154 (0%)		0/155 (0%)		2/152 (1.3%)		0/154 (0%)		0/155 (0%)		2/152 (1.3%)
Chest pain	3/154 (1.9%)		1/155 (0.6%)		4/152 (2.6%)		4/154 (2.6%)		1/155 (0.6%)		4/152 (2.6%)
Death	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Device failure	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Device malfunction	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Drug withdrawal syndrome	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Generalised oedema	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Medical device complication	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Multi-organ failure	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Non-cardiac chest pain	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Oedema peripheral	2/154 (1.3%)		0/155 (0%)		1/152 (0.7%)		2/154 (1.3%)		0/155 (0%)		1/152 (0.7%)
Pyrexia	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Sudden cardiac death	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Systemic inflammatory response syndrome	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Hepatobiliary disorders
Cholecystitis acute	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Cholecystitis chronic	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Cholelithiasis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		1/152 (0.7%)
Gallbladder cholesterolosis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Infections and infestations
Abscess limb	2/154 (1.3%)		2/155 (1.3%)		2/152 (1.3%)		2/154 (1.3%)		2/155 (1.3%)		2/152 (1.3%)
Appendicitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Appendicitis perforated	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Arthritis bacterial	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Breast cellulitis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Bronchitis	1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)		1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)
Burn infection	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Cellulitis	4/154 (2.6%)		7/155 (4.5%)		8/152 (5.3%)		5/154 (3.2%)		9/155 (5.8%)		8/152 (5.3%)
Chronic sinusitis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Clostridium difficile infection	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Diabetic foot infection	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Diverticulitis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Endocarditis bacterial	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Endophthalmitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Endophthalmitis	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Enterococcal bacteraemia	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Escherichia urinary tract infection	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Gangrene	0/154 (0%)		2/155 (1.3%)		1/152 (0.7%)		2/154 (1.3%)		2/155 (1.3%)		2/152 (1.3%)
Gastroenteritis	1/154 (0.6%)		1/155 (0.6%)		2/152 (1.3%)		1/154 (0.6%)		1/155 (0.6%)		2/152 (1.3%)
Gastroenteritis viral	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Infected skin ulcer	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Infection	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Influenza	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Klebsiella sepsis	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Lobar pneumonia	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		3/155 (1.9%)		0/152 (0%)
Localised infection	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Mastoiditis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Osteomyelitis	3/154 (1.9%)		5/155 (3.2%)		2/152 (1.3%)		5/154 (3.2%)		7/155 (4.5%)		3/152 (2%)
Osteomyelitis acute	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Parotitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Perineal abscess	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Pneumonia	4/154 (2.6%)		4/155 (2.6%)		3/152 (2%)		4/154 (2.6%)		6/155 (3.9%)		4/152 (2.6%)
Pneumonia bacterial	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Pyelonephritis	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Sepsis	2/154 (1.3%)		2/155 (1.3%)		0/152 (0%)		2/154 (1.3%)		3/155 (1.9%)		0/152 (0%)
Sinusitis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Staphylococcal bacteraemia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Staphylococcal infection	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Staphylococcal sepsis	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Urinary tract infection	2/154 (1.3%)		0/155 (0%)		0/152 (0%)		4/154 (2.6%)		2/155 (1.3%)		1/152 (0.7%)
Urosepsis	1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)		1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)
Wound sepsis	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Injury, poisoning and procedural complications
Accident	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Accidental overdose	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Ankle fracture	0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		2/152 (1.3%)
Arteriovenous fistula site complication	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Arteriovenous fistula site haemorrhage	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Arteriovenous graft site haemorrhage	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Cataract operation complication	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Cataract traumatic	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Clavical fracture	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Concussion	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Craniocerebral injury	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Fall	2/154 (1.3%)		3/155 (1.9%)		5/152 (3.3%)		3/154 (1.9%)		3/155 (1.9%)		5/152 (3.3%)
Femoral neck fracture	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Femur fracture	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Humerus fracture	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Incisional hernia	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Laceration	0/154 (0%)		2/155 (1.3%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Lower limb fracture	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Lumbar vertebral fracture	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Meniscus injury	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Pelvic fracture	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Procedural pain	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Radius fracture	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Rib fracture	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Road traffic accident	1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)		1/154 (0.6%)		2/155 (1.3%)		1/152 (0.7%)
Seroma	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Spinal compression fracture	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Spinal fracture	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Subdural haematoma	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Thoracic vertebral fracture	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ulna fracture	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Wound haemorrhage	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Investigations
Blood creatinine increased	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Haematocrit decreased	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Haemoglobin decreased	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Heart rate increased	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
International normalised ratio increased	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Intraocular pressure increased	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Transaminases increased	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Troponin increased	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Visual acuity tests abnormal	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		0/152 (0%)
Metabolism and nutrition disorders
Dehydration	1/154 (0.6%)		2/155 (1.3%)		2/152 (1.3%)		4/154 (2.6%)		2/155 (1.3%)		2/152 (1.3%)
Diabetes mellitus inadequate control	0/154 (0%)		3/155 (1.9%)		2/152 (1.3%)		0/154 (0%)		4/155 (2.6%)		2/152 (1.3%)
Diabetes with hyperosmolarity	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Diabetic ketoacidosis	1/154 (0.6%)		2/155 (1.3%)		2/152 (1.3%)		1/154 (0.6%)		2/155 (1.3%)		2/152 (1.3%)
Failure to thrive	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Fluid overload	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Fluid retention	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Hyperglycaemia	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)
Hyperkalaemia	4/154 (2.6%)		3/155 (1.9%)		1/152 (0.7%)		6/154 (3.9%)		4/155 (2.6%)		1/152 (0.7%)
Hypoglycaemia	1/154 (0.6%)		5/155 (3.2%)		0/152 (0%)		1/154 (0.6%)		6/155 (3.9%)		0/152 (0%)
Hypokalaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Ketosis	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Metabolic acidosis	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Obesity	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		0/152 (0%)
Arthritis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Back pain	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)
Cervical spinal stenosis	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Intervertebral disc degeneration	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Intervertebral disc protrusion	0/154 (0%)		1/155 (0.6%)		2/152 (1.3%)		0/154 (0%)		1/155 (0.6%)		2/152 (1.3%)
Joint effusion	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Musculoskeletal chest pain	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Neuropathic arthropathy	0/154 (0%)		2/155 (1.3%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Osteoarthritis	3/154 (1.9%)		4/155 (2.6%)		0/152 (0%)		3/154 (1.9%)		5/155 (3.2%)		0/152 (0%)
Spinal column stenosis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Spinal osteoarthritis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Tendon disorder	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Tendonitits	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Bladder cancer stage II	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Breast cancer	0/154 (0%)		3/155 (1.9%)		0/152 (0%)		0/154 (0%)		3/155 (1.9%)		0/152 (0%)
Breast cancer metastatic	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Chronic myeloid leukaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Chronic myelomonocytic leukaemia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Clear cell renal cell carcinoma	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Diffuse large B-cell lymphoma stage III	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Invasive ductal breast carcinoma	0/154 (0%)		1/155 (0.6%)		3/152 (2%)		0/154 (0%)		1/155 (0.6%)		3/152 (2%)
Malignant melanoma	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Melanocytic naevus	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		0/152 (0%)
Myelodysplastic syndrome	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Prostate cancer	0/154 (0%)		3/155 (1.9%)		0/152 (0%)		0/154 (0%)		3/155 (1.9%)		1/152 (0.7%)
Prostate cancer recurrent	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Rectal adenocarcinoma	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Rectal neoplasm	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Renal cancer	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Squamous cell carcinoma of skin	0/154 (0%)		1/155 (0.6%)		2/152 (1.3%)		0/154 (0%)		1/155 (0.6%)		2/152 (1.3%)
Nervous system disorders
Amnesia	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Ataxia	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Autonomic nervous system imbalance	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Brain injury	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Brain stem stroke	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Carotid artery stenosis	0/154 (0%)		2/155 (1.3%)		0/152 (0%)		0/154 (0%)		2/155 (1.3%)		0/152 (0%)
Cerebral infarction	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Cerebrovascular accident	2/154 (1.3%)		5/155 (3.2%)		5/152 (3.3%)		4/154 (2.6%)		5/155 (3.2%)		5/152 (3.3%)
Cognitive disorder	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Coma	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Convulsion	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		1/152 (0.7%)
Diabetic coma	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Dizziness	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Encephalopathy	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Haemorrhage intracranial	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Headache	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Hemianopia homonymous	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Hypertensive encephalopathy	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ischaemic cerebral infarction	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Ischaemic stroke	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		1/152 (0.7%)
Lacunar infarction	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Lumbar radiculopathy	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Metabolic encephalopathy	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Multiple sclerosis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Normal pressure hydrocephalus	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Presyncope	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Sciatica	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Sedation	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Syncope	2/154 (1.3%)		2/155 (1.3%)		0/152 (0%)		3/154 (1.9%)		3/155 (1.9%)		1/152 (0.7%)
Thalamic infarction	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Toxic encephalopathy	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Transient ischaemic attack	3/154 (1.9%)		0/155 (0%)		1/152 (0.7%)		3/154 (1.9%)		1/155 (0.6%)		1/152 (0.7%)
VIIth nerve paralysis	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Visual field defect	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Psychiatric disorders
Affective disorder	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Confusional state	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Depression	2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)
Disorientation	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Mental status changes	0/154 (0%)		2/155 (1.3%)		1/152 (0.7%)		0/154 (0%)		2/155 (1.3%)		1/152 (0.7%)
Schizoaffective disorder	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Renal and urinary disorders
Azotaemia	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Bladder outlet obstruction	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Calculus ureteric	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Haematuria	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Intercapillary glomerulosclerosis	0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Nephrolithiasis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Nephropathy	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Nephropathy toxic	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Nephrosclerosis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Nephrotic syndrome	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Renal failure	4/154 (2.6%)		5/155 (3.2%)		1/152 (0.7%)		5/154 (3.2%)		5/155 (3.2%)		1/152 (0.7%)
Renal failure acute	7/154 (4.5%)		6/155 (3.9%)		6/152 (3.9%)		9/154 (5.8%)		10/155 (6.5%)		8/152 (5.3%)
Renal failure chronic	2/154 (1.3%)		4/155 (2.6%)		3/152 (2%)		4/154 (2.6%)		5/155 (3.2%)		3/152 (2%)
Renal impairment	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Renal tubular necrosis	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Ureteric stenosis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Urinary retention	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Reproductive system and breast disorders
Breast mass	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		0/152 (0%)
Endometrial hyperplasia	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Labia enlarged	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Menorrhagia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Postmenopausal haemorrhage	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Uterine mass	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Acute respiratory failure	0/154 (0%)		1/155 (0.6%)		1/152 (0.7%)		2/154 (1.3%)		2/155 (1.3%)		1/152 (0.7%)
Asthma	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Atelectasis	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Bronchiectasis	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Chronic obstructive pulmonary disease	2/154 (1.3%)		0/155 (0%)		0/152 (0%)		2/154 (1.3%)		0/155 (0%)		0/152 (0%)
Dyspnoea	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Hypoxia	0/154 (0%)		2/155 (1.3%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Pleural effusion	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Pulmonary embolism	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Pulmonary fibrosis	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Pulmonary oedema	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Respiratory distress	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Diabetic foot	0/154 (0%)		2/155 (1.3%)		2/152 (1.3%)		0/154 (0%)		3/155 (1.9%)		2/152 (1.3%)
Hypertrophic scar	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Skin ulcer	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)
Surgical and medical procedures
Arteriovenous fistula operation	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Coronary artery bypass	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		0/155 (0%)		0/152 (0%)
Foot amputation	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Vascular disorders
Arteriosclerosis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Deep vein thrombosis	0/154 (0%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Haematoma	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Hypertension	3/154 (1.9%)		5/155 (3.2%)		1/152 (0.7%)		3/154 (1.9%)		6/155 (3.9%)		2/152 (1.3%)
Hypertensive crisis	2/154 (1.3%)		2/155 (1.3%)		0/152 (0%)		2/154 (1.3%)		2/155 (1.3%)		0/152 (0%)
Hypertensive emergency	1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		1/155 (0.6%)		0/152 (0%)
Hypotension	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		1/154 (0.6%)		2/155 (1.3%)		0/152 (0%)
Hypovolaemic shock	1/154 (0.6%)		0/155 (0%)		0/152 (0%)		1/154 (0.6%)		0/155 (0%)		0/152 (0%)
Intermittent claudication	0/154 (0%)		1/155 (0.6%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Malignant hypertension	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		1/154 (0.6%)		1/155 (0.6%)		1/152 (0.7%)
Orthostatic hypotension	2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)		2/154 (1.3%)		1/155 (0.6%)		0/152 (0%)
Peripheral arterial occlusive disease	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Peripheral artery stenosis	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Peripheral ischaemia	0/154 (0%)		0/155 (0%)		0/152 (0%)		0/154 (0%)		1/155 (0.6%)		0/152 (0%)
Peripheral vascular disorder	0/154 (0%)		0/155 (0%)		1/152 (0.7%)		0/154 (0%)		0/155 (0%)		1/152 (0.7%)
Other (Not Including Serious) Adverse Events
	Control (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 100)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 100)		Control (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321 2Q4 (Week 0 to Week 148)		IAI;EYLEA®;BAY86-5321) 2Q8 (Week 0 to Week 148)
	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	91/154 (59.1%)		90/155 (58.1%)		76/152 (50%)		134/154 (87%)		137/155 (88.4%)		136/152 (89.5%)
Blood and lymphatic system disorders
Anaemia	12/154 (7.8%)		20/155 (12.9%)		12/152 (7.9%)		15/154 (9.7%)		27/155 (17.4%)		20/152 (13.2%)
Cardiac disorders
Cardiac failure congestive	6/154 (3.9%)		12/155 (7.7%)		9/152 (5.9%)		4/154 (2.6%)		6/155 (3.9%)		8/152 (5.3%)
Endocrine disorders
Hypothyroidism	7/154 (4.5%)		4/155 (2.6%)		5/152 (3.3%)		8/154 (5.2%)		4/155 (2.6%)		5/152 (3.3%)
Eye disorders
Cataract	17/154 (11%)		15/155 (9.7%)		11/152 (7.2%)		25/154 (16.2%)		22/155 (14.2%)		17/152 (11.2%)
Cataract	16/154 (10.4%)		21/155 (13.5%)		13/152 (8.6%)		24/154 (15.6%)		28/155 (18.1%)		21/152 (13.8%)
Cataract cortical	6/154 (3.9%)		3/155 (1.9%)		6/152 (3.9%)		11/154 (7.1%)		2/155 (1.3%)		7/152 (4.6%)
Cataract cortical	8/154 (5.2%)		2/155 (1.3%)		7/152 (4.6%)		8/154 (5.2%)		5/155 (3.2%)		7/152 (4.6%)
Cataract nuclear	2/154 (1.3%)		6/155 (3.9%)		2/152 (1.3%)		6/154 (3.9%)		8/155 (5.2%)		3/152 (2%)
Cataract nuclear	2/154 (1.3%)		6/155 (3.9%)		2/152 (1.3%)		2/154 (1.3%)		8/155 (5.2%)		2/152 (1.3%)
Cataract subcapsular	6/154 (3.9%)		4/155 (2.6%)		8/152 (5.3%)		8/154 (5.2%)		8/155 (5.2%)		10/152 (6.6%)
Cataract subcapsular	7/154 (4.5%)		6/155 (3.9%)		8/152 (5.3%)		10/154 (6.5%)		12/155 (7.7%)		10/152 (6.6%)
Conjunctival haemorrhage	29/154 (18.8%)		30/155 (19.4%)		27/152 (17.8%)		31/154 (20.1%)		35/155 (22.6%)		29/152 (19.1%)
Conjunctival haemorrhage	53/154 (34.4%)		63/155 (40.6%)		48/152 (31.6%)		55/154 (35.7%)		63/155 (40.6%)		50/152 (32.9%)
Corneal abrasion	6/154 (3.9%)		4/155 (2.6%)		6/152 (3.9%)		9/154 (5.8%)		7/155 (4.5%)		6/152 (3.9%)
Diabetic retinal oedema	19/154 (12.3%)		22/155 (14.2%)		18/152 (11.8%)		26/154 (16.9%)		29/155 (18.7%)		23/152 (15.1%)
Diabetic retinopathy	11/154 (7.1%)		8/155 (5.2%)		14/152 (9.2%)		16/154 (10.4%)		8/155 (5.2%)		18/152 (11.8%)
Dry eye	7/154 (4.5%)		12/155 (7.7%)		7/152 (4.6%)		8/154 (5.2%)		13/155 (8.4%)		9/152 (5.9%)
Dry eye	10/154 (6.5%)		14/155 (9%)		7/152 (4.6%)		12/154 (7.8%)		16/155 (10.3%)		9/152 (5.9%)
Eye irritation	12/154 (7.8%)		15/155 (9.7%)		11/152 (7.2%)		14/154 (9.1%)		15/155 (9.7%)		13/152 (8.6%)
Eye irritation	7/154 (4.5%)		6/155 (3.9%)		7/152 (4.6%)		8/154 (5.2%)		9/155 (5.8%)		8/152 (5.3%)
Eye pain	20/154 (13%)		23/155 (14.8%)		21/152 (13.8%)		23/154 (14.9%)		23/155 (14.8%)		26/152 (17.1%)
Eye pain	7/154 (4.5%)		11/155 (7.1%)		9/152 (5.9%)		10/154 (6.5%)		13/155 (8.4%)		14/152 (9.2%)
Foreign body sensation in eyes	8/154 (5.2%)		8/155 (5.2%)		5/152 (3.3%)		8/154 (5.2%)		9/155 (5.8%)		6/152 (3.9%)
Lacrimation increased	3/154 (1.9%)		4/155 (2.6%)		7/152 (4.6%)		4/154 (2.6%)		5/155 (3.2%)		9/152 (5.9%)
Lacrimation increased	6/154 (3.9%)		7/155 (4.5%)		6/152 (3.9%)		7/154 (4.5%)		8/155 (5.2%)		8/152 (5.3%)
Macular fibrosis	15/154 (9.7%)		11/155 (7.1%)		15/152 (9.9%)		20/154 (13%)		13/155 (8.4%)		17/152 (11.2%)
Macular fibrosis	12/154 (7.8%)		11/155 (7.1%)		16/152 (10.5%)		19/154 (12.3%)		14/155 (9%)		23/152 (15.1%)
Macular oedema	1/154 (0.6%)		4/155 (2.6%)		6/152 (3.9%)		7/154 (4.5%)		6/155 (3.9%)		9/152 (5.9%)
Ocular hyperaemia	12/154 (7.8%)		6/155 (3.9%)		6/152 (3.9%)		12/154 (7.8%)		6/155 (3.9%)		7/152 (4.6%)
Pain in extremity	10/154 (6.5%)		8/155 (5.2%)		5/152 (3.3%)		13/154 (8.4%)		12/155 (7.7%)		7/152 (4.6%)
Photopsia	7/154 (4.5%)		2/155 (1.3%)		1/152 (0.7%)		8/154 (5.2%)		2/155 (1.3%)		2/152 (1.3%)
Posterior capsule opacification	10/154 (6.5%)		5/155 (3.2%)		5/152 (3.3%)		12/154 (7.8%)		8/155 (5.2%)		10/152 (6.6%)
Posterior capsule opacification	12/154 (7.8%)		7/155 (4.5%)		8/152 (5.3%)		16/154 (10.4%)		9/155 (5.8%)		15/152 (9.9%)
Punctate keratitis	1/154 (0.6%)		5/155 (3.2%)		7/152 (4.6%)		3/154 (1.9%)		8/155 (5.2%)		7/152 (4.6%)
Retinal exudates	13/154 (8.4%)		12/155 (7.7%)		4/152 (2.6%)		14/154 (9.1%)		15/155 (9.7%)		6/152 (3.9%)
Retinal exudates	11/154 (7.1%)		12/155 (7.7%)		6/152 (3.9%)		15/154 (9.7%)		15/155 (9.7%)		8/152 (5.3%)
Retinal haemorrhage	15/154 (9.7%)		10/155 (6.5%)		5/152 (3.3%)		16/154 (10.4%)		13/155 (8.4%)		7/152 (4.6%)
Retinal haemorrhage	10/154 (6.5%)		11/155 (7.1%)		5/152 (3.3%)		13/154 (8.4%)		16/155 (10.3%)		6/152 (3.9%)
Retinal neovascularisation	10/154 (6.5%)		10/155 (6.5%)		4/152 (2.6%)		12/154 (7.8%)		10/155 (6.5%)		5/152 (3.3%)
Retinal neovascularisation	12/154 (7.8%)		3/155 (1.9%)		3/152 (2%)		12/154 (7.8%)		3/155 (1.9%)		3/152 (2%)
Retinal pigment epitheliopathy	3/154 (1.9%)		5/155 (3.2%)		8/152 (5.3%)		3/154 (1.9%)		6/155 (3.9%)		9/152 (5.9%)
Vision blurred	10/154 (6.5%)		11/155 (7.1%)		6/152 (3.9%)		13/154 (8.4%)		14/155 (9%)		9/152 (5.9%)
Vision blurred	5/154 (3.2%)		8/155 (5.2%)		5/152 (3.3%)		7/154 (4.5%)		11/155 (7.1%)		7/152 (4.6%)
Visual Impairment	7/154 (4.5%)		1/155 (0.6%)		3/152 (2%)		8/154 (5.2%)		1/155 (0.6%)		3/152 (2%)
Visual acuity reduced	6/154 (3.9%)		4/155 (2.6%)		10/152 (6.6%)		10/154 (6.5%)		8/155 (5.2%)		10/152 (6.6%)
Visual acuity reduced	11/154 (7.1%)		7/155 (4.5%)		10/152 (6.6%)		14/154 (9.1%)		10/155 (6.5%)		12/152 (7.9%)
Vitreous detachment	16/154 (10.4%)		15/155 (9.7%)		18/152 (11.8%)		23/154 (14.9%)		17/155 (11%)		23/152 (15.1%)
Vitreous detachment	15/154 (9.7%)		14/155 (9%)		22/152 (14.5%)		20/154 (13%)		20/155 (12.9%)		25/152 (16.4%)
Vitreous floaters	10/154 (6.5%)		11/155 (7.1%)		10/152 (6.6%)		12/154 (7.8%)		15/155 (9.7%)		14/152 (9.2%)
Vitreous floaters	14/154 (9.1%)		21/155 (13.5%)		17/152 (11.2%)		16/154 (10.4%)		23/155 (14.8%)		21/152 (13.8%)
Vitreous haemorrhage	12/154 (7.8%)		9/155 (5.8%)		2/152 (1.3%)		13/154 (8.4%)		10/155 (6.5%)		4/152 (2.6%)
Vitreous haemorrhage	11/154 (7.1%)		8/155 (5.2%)		5/152 (3.3%)		19/154 (12.3%)		11/155 (7.1%)		7/152 (4.6%)
Gastrointestinal disorders
Constipation	9/154 (5.8%)		11/155 (7.1%)		5/152 (3.3%)		14/154 (9.1%)		15/155 (9.7%)		6/152 (3.9%)
Diarrhoea	13/154 (8.4%)		14/155 (9%)		6/152 (3.9%)		15/154 (9.7%)		19/155 (12.3%)		7/152 (4.6%)
Gastrooesophageal reflux disease	9/154 (5.8%)		10/155 (6.5%)		4/152 (2.6%)		14/154 (9.1%)		13/155 (8.4%)		10/152 (6.6%)
Nausea	15/154 (9.7%)		19/155 (12.3%)		11/152 (7.2%)		16/154 (10.4%)		21/155 (13.5%)		16/152 (10.5%)
Vomiting	7/154 (4.5%)		14/155 (9%)		3/152 (2%)		9/154 (5.8%)		16/155 (10.3%)		5/152 (3.3%)
General disorders
Chest pain	9/154 (5.8%)		3/155 (1.9%)		5/152 (3.3%)		9/154 (5.8%)		3/155 (1.9%)		5/152 (3.3%)
Fatigue	4/154 (2.6%)		8/155 (5.2%)		3/152 (2%)		5/154 (3.2%)		9/155 (5.8%)		3/152 (2%)
Oedema peripheral	8/154 (5.2%)		15/155 (9.7%)		15/152 (9.9%)		11/154 (7.1%)		19/155 (12.3%)		16/152 (10.5%)
Pyrexia	2/154 (1.3%)		7/155 (4.5%)		6/152 (3.9%)		5/154 (3.2%)		10/155 (6.5%)		7/152 (4.6%)
Immune system disorders
Drug hypersensitivity	2/154 (1.3%)		5/155 (3.2%)		3/152 (2%)		6/154 (3.9%)		8/155 (5.2%)		3/152 (2%)
Seasonal allergy	8/154 (5.2%)		6/155 (3.9%)		9/152 (5.9%)		9/154 (5.8%)		9/155 (5.8%)		12/152 (7.9%)
Infections and infestations
Bronchitis	11/154 (7.1%)		12/155 (7.7%)		4/152 (2.6%)		13/154 (8.4%)		12/155 (7.7%)		7/152 (4.6%)
Cellulitis	7/154 (4.5%)		10/155 (6.5%)		12/152 (7.9%)		7/154 (4.5%)		5/155 (3.2%)		8/152 (5.3%)
Ear infection	4/154 (2.6%)		3/155 (1.9%)		6/152 (3.9%)		6/154 (3.9%)		5/155 (3.2%)		9/152 (5.9%)
Gastroenteritis viral	2/154 (1.3%)		2/155 (1.3%)		6/152 (3.9%)		2/154 (1.3%)		3/155 (1.9%)		8/152 (5.3%)
Influenza	9/154 (5.8%)		7/155 (4.5%)		16/152 (10.5%)		15/154 (9.7%)		9/155 (5.8%)		22/152 (14.5%)
Localised infection	5/154 (3.2%)		10/155 (6.5%)		5/152 (3.3%)		11/154 (7.1%)		11/155 (7.1%)		5/152 (3.3%)
Nasopharyngitis	17/154 (11%)		17/155 (11%)		19/152 (12.5%)		23/154 (14.9%)		22/155 (14.2%)		24/152 (15.8%)
Pneumonia	7/154 (4.5%)		8/155 (5.2%)		7/152 (4.6%)		4/154 (2.6%)		9/155 (5.8%)		6/152 (3.9%)
Sinusitis	12/154 (7.8%)		13/155 (8.4%)		12/152 (7.9%)		18/154 (11.7%)		14/155 (9%)		13/152 (8.6%)
Upper respiratory tract infection	13/154 (8.4%)		11/155 (7.1%)		15/152 (9.9%)		16/154 (10.4%)		13/155 (8.4%)		17/152 (11.2%)
Urinary tract infection	14/154 (9.1%)		17/155 (11%)		26/152 (17.1%)		20/154 (13%)		30/155 (19.4%)		32/152 (21.1%)
Injury, poisoning and procedural complications
Fall	8/154 (5.2%)		7/155 (4.5%)		12/152 (7.9%)		12/154 (7.8%)		7/155 (4.5%)		14/152 (9.2%)
Procedural pain	1/154 (0.6%)		8/155 (5.2%)		2/152 (1.3%)		2/154 (1.3%)		8/155 (5.2%)		3/152 (2%)
Investigations
Blood creatine phosphokinase increased	12/154 (7.8%)		7/155 (4.5%)		4/152 (2.6%)		12/154 (7.8%)		9/155 (5.8%)		4/152 (2.6%)
Blood glucose increased	6/154 (3.9%)		9/155 (5.8%)		11/152 (7.2%)		9/154 (5.8%)		15/155 (9.7%)		16/152 (10.5%)
Blood pressure increased	10/154 (6.5%)		9/155 (5.8%)		7/152 (4.6%)		15/154 (9.7%)		12/155 (7.7%)		8/152 (5.3%)
Blood pressure systolic increased	2/154 (1.3%)		2/155 (1.3%)		5/152 (3.3%)		2/154 (1.3%)		4/155 (2.6%)		8/152 (5.3%)
Glycosylated haemoglobin increased	7/154 (4.5%)		7/155 (4.5%)		13/152 (8.6%)		10/154 (6.5%)		10/155 (6.5%)		16/152 (10.5%)
Intraocular pressure increased	2/154 (1.3%)		12/155 (7.7%)		10/152 (6.6%)		6/154 (3.9%)		16/155 (10.3%)		10/152 (6.6%)
Urine protein/ creatinine ratio increased	8/154 (5.2%)		5/155 (3.2%)		2/152 (1.3%)		9/154 (5.8%)		8/155 (5.2%)		3/152 (2%)
Metabolism and nutrition disorders
Diabetes mellitus	20/154 (13%)		13/155 (8.4%)		19/152 (12.5%)		28/154 (18.2%)		23/155 (14.8%)		25/152 (16.4%)
Hypercholesterolaemia	10/154 (6.5%)		5/155 (3.2%)		3/152 (2%)		13/154 (8.4%)		6/155 (3.9%)		4/152 (2.6%)
Hyperkalaemia	9/154 (5.8%)		9/155 (5.8%)		6/152 (3.9%)		9/154 (5.8%)		11/155 (7.1%)		8/152 (5.3%)
Hypoglycaemia	3/154 (1.9%)		8/155 (5.2%)		5/152 (3.3%)		10/154 (6.5%)		14/155 (9%)		9/152 (5.9%)
Type 2 diabetes mellitus	6/154 (3.9%)		9/155 (5.8%)		5/152 (3.3%)		9/154 (5.8%)		12/155 (7.7%)		6/152 (3.9%)
Vitamin D deficiency	7/154 (4.5%)		6/155 (3.9%)		5/152 (3.3%)		7/154 (4.5%)		8/155 (5.2%)		7/152 (4.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/154 (5.8%)		8/155 (5.2%)		8/152 (5.3%)		12/154 (7.8%)		13/155 (8.4%)		9/152 (5.9%)
Arthritis	6/154 (3.9%)		5/155 (3.2%)		10/152 (6.6%)		7/154 (4.5%)		6/155 (3.9%)		12/152 (7.9%)
Back pain	8/154 (5.2%)		20/155 (12.9%)		6/152 (3.9%)		11/154 (7.1%)		22/155 (14.2%)		9/152 (5.9%)
Muscle spasms	8/154 (5.2%)		5/155 (3.2%)		2/152 (1.3%)		9/154 (5.8%)		6/155 (3.9%)		4/152 (2.6%)
Osteoarthritis	7/154 (4.5%)		7/155 (4.5%)		5/152 (3.3%)		6/154 (3.9%)		4/155 (2.6%)		12/152 (7.9%)
Nervous system disorders
Dizziness	8/154 (5.2%)		7/155 (4.5%)		9/152 (5.9%)		9/154 (5.8%)		9/155 (5.8%)		10/152 (6.6%)
Headache	19/154 (12.3%)		18/155 (11.6%)		7/152 (4.6%)		22/154 (14.3%)		21/155 (13.5%)		13/152 (8.6%)
Neuropathy peripheral	5/154 (3.2%)		5/155 (3.2%)		7/152 (4.6%)		6/154 (3.9%)		6/155 (3.9%)		8/152 (5.3%)
Psychiatric disorders
Anxiety	7/154 (4.5%)		12/155 (7.7%)		4/152 (2.6%)		9/154 (5.8%)		13/155 (8.4%)		5/152 (3.3%)
Depression	7/154 (4.5%)		7/155 (4.5%)		4/152 (2.6%)		9/154 (5.8%)		6/155 (3.9%)		4/152 (2.6%)
Renal and urinary disorders
Renal failure acute	11/154 (7.1%)		10/155 (6.5%)		9/152 (5.9%)		5/154 (3.2%)		8/155 (5.2%)		7/152 (4.6%)
Renal failure chronic	4/154 (2.6%)		9/155 (5.8%)		8/152 (5.3%)		5/154 (3.2%)		9/155 (5.8%)		8/152 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	13/154 (8.4%)		18/155 (11.6%)		17/152 (11.2%)		16/154 (10.4%)		21/155 (13.5%)		20/152 (13.2%)
Dyspnoea	6/154 (3.9%)		12/155 (7.7%)		11/152 (7.2%)		7/154 (4.5%)		15/155 (9.7%)		13/152 (8.6%)
Vascular disorders
Hypertension	49/154 (31.8%)		41/155 (26.5%)		42/152 (27.6%)		56/154 (36.4%)		51/155 (32.9%)		49/152 (32.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Not less than 45 days prior to submission of any (M)anuscript, (I)nstitution shall, or cause PI to, provide (S)ponsor a copy of (M). (I) to consider comments submitted by (S), & to delete confidential information upon (S) request. At (S)'s request, (I) to delay publication for an additional 60 days to allow filing of patent applications. (I) & PI agree to delay publication, prior to (M) summarizing data from all sites, unless no (M) is published prior to first anniversary of final study report.