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Clinical Trial Results:
A randomized, double masked, active controlled, phase III study of the efficacy and safety of repeated doses of intravitreal VEGF Trap-Eye in subjects with diabetic macular edema

Summary
EudraCT number	2010-022364-12
Trial protocol	DE AT CZ ES DK IT HU
Global end of trial date	30 Mar 2015

Results information
Results version number	v2(current)
This version publication date	04 Sep 2016
First version publication date	06 Apr 2016
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Bayer sponsor contact information to be updated

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BAY86-5321/91745

ISRCTN number

US NCT number

NCT01331681

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Mar 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to assess the efficacy of intravitreal (IVT) administered vascular endothelial growth factor (VEGF) Trap–Eye in comparison to macular laser photocoagulation treatment in improving best corrected visual acuity (BCVA) in subjects with diabetic macular edema (DME).

Protection of trial subjects

The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 May 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 77

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Austria: 15

Country: Number of subjects enrolled

Czech Republic: 39

Country: Number of subjects enrolled

Germany: 52

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Spain: 57

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

Hungary: 76

Country: Number of subjects enrolled

Italy: 27

Country: Number of subjects enrolled

Poland: 14

Worldwide total number of subjects

406

EEA total number of subjects

311

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

214

From 65 to 84 years

192

85 years and over

Subject disposition

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Recruitment details

Subjects with diabetic macular edema (DME) secondary to diabetes mellitus involving the center of the macula in the study eye could participate in the study. The study was conducted at 73 study centers in Japan, European Countries and Australia in subjects between 09 May 2011 (first subject first visit) and 30 Mar 2015 (last subject last visit).

Screening details

Of 604 subjects who were screened for inclusion in the study, 406 were randomized, and 404 received treatment.

Number of subjects started

406

Number of subjects completed

404

Reason: Number of subjects

Not Received Study Treatment: 2

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Intravitreal Aflibercept Injection 2Q4

Arm description

Subjects received 2 milligram (mg) Intravitreal aflibercept injection (IAI) (EYLEA, vascular endothelial growth factor [VEGF] Trap-Eye, BAY86-5321) every 4 weeks (2Q4).

Arm type

Experimental

Investigational medicinal product name

VEGF Trap-Eye

Investigational medicinal product code

BAY86-5321

Other name

Aflibercept and Eylea

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Subjects received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) 2Q4.

Intravitreal Aflibercept Injection 2Q8

Arm description

Subjects received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).

Arm type

Experimental

Investigational medicinal product name

VEGF Trap-Eye

Investigational medicinal product code

BAY86-5321

Other name

Aflibercept and Eylea

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Subjects received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections 2Q8.

Macular Laser Photocoagulation (Control)

Arm description

Subjects received 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. During year 3 laser subjects could receive IAI as needed (PRN).

Arm type

Procedure

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1 ^[1]	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Started	136	135	133
Completed Week 52	125	121	115
Completed Week 100	115	110	105
Completed Week 148	101	101	100
Completed	101	101	100
Not completed	35	34	33
Physician decision	2	-	4
Adverse Event	10	13	10
Death	6	6	2
Switching to other therapy	-	-	1
Withdrawal by Subject	12	8	15
Lost to follow-up	2	4	1
Sponsor decision	1	1	-
Therapeutic procedure required	1	-	-
Protocol deviation	1	1	-
Lack of efficacy	-	1	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Worldwide number of subjects is equal to the number of subjects in the pre-assignment period and the baseline period starts with the number of subjects received the treatment.

Baseline characteristics

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Reporting group title

Intravitreal Aflibercept Injection 2Q4

Reporting group description

Subjects received 2 milligram (mg) Intravitreal aflibercept injection (IAI) (EYLEA, vascular endothelial growth factor [VEGF] Trap-Eye, BAY86-5321) every 4 weeks (2Q4).

Reporting group title

Intravitreal Aflibercept Injection 2Q8

Reporting group description

Subjects received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).

Reporting group title

Macular Laser Photocoagulation (Control)

Reporting group description

Reporting group values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)	Total
Number of subjects	136	135	133	404
Age categorical
Units: Subjects
Age continous
Age continuous
Units: years
arithmetic mean (standard deviation)	62.6 ( 8.6 )	64.2 ( 7.7 )	63.9 ( 8.6 )	-
Gender
Units: subjects
Female	53	47	54	154
Male	83	88	79	250

End points

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Reporting group title

Intravitreal Aflibercept Injection 2Q4

Reporting group description

Subjects received 2 milligram (mg) Intravitreal aflibercept injection (IAI) (EYLEA, vascular endothelial growth factor [VEGF] Trap-Eye, BAY86-5321) every 4 weeks (2Q4).

Reporting group title

Intravitreal Aflibercept Injection 2Q8

Reporting group description

Subjects received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).

Reporting group title

Macular Laser Photocoagulation (Control)

Reporting group description

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

SAF included all subjects who received at least 1 study treatment (active or sham). Treatment administration/compliance and all clinical safety and tolerability variables were analyzed using the SAF.

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS included all randomized subjects who received any study treatment, had a baseline measurement of BCVA, and had at least 1 post-baseline assessment of BCVA. All efficacy endpoints were analyzed using the FAS.

Primary: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF)

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End point title

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

End point description

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

End point type

Primary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[1]	135 ^[2]	132 ^[3]
Units: letters correctly read
arithmetic mean (standard deviation)	10.5 ( 9.55 )	10.7 ( 9.32 )	1.2 ( 10.65 )

Notes
[1] - FAS
[2] - FAS
[3] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

< 0.0001 ^[5]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

9.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.5

upper limit

Notes
[4] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. Least square (LS) mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[5] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value was below the significance level of 0.025, the fixed sequence testing did continue with the first secondary endpoint.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

< 0.0001 ^[7]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

9.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.3

upper limit

11.8

Notes
[6] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[7] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value was below the significance level of 0.025, the fixed sequence testing did continue with the first secondary endpoint.

Secondary: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

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End point title

Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

End point description

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

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[8]	135 ^[9]	132 ^[10]
Units: percentage of subjects
number (not applicable)	54.4	53.3	25.8

Notes
[8] - FAS
[9] - FAS
[10] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Probability to gain >= 10 letters identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

< 0.0001 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

28.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

15.8

upper limit

41.6

Notes
[11] - stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[12] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the second secondary endpoint.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Probability to gain >= 10 letters identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

< 0.0001 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

27.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

14.6

upper limit

40.5

Notes
[13] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[14] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the second secondary endpoint.

Secondary: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

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End point title

Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

End point description

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

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[15]	135 ^[16]	132 ^[17]
Units: percentage of subjects
number (not applicable)	32.4	33.3	9.1

Notes
[15] - FAS
[16] - FAS
[17] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Probability to gain >= 15 letters identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

< 0.0001 ^[19]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

23.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

12.6

upper limit

33.9

Notes
[18] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[19] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the third secondary endpoint.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Probability to gain >= 15 letters identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

< 0.0001 ^[21]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

24.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

13.5

upper limit

34.9

Notes
[20] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[21] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the third secondary endpoint.

Secondary: Percentage of Subjects 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

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End point title

Percentage of Subjects 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

End point 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)

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	81 ^[22]	83 ^[23]	80 ^[24]
Units: percentage of subjects
number (not applicable)	33.3	27.7	7.5

Notes
[22] - FAS with assessment for this end-point.
[23] - FAS with assessment for this end-point.
[24] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Probability to improve by >= 2 steps identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001 ^[26]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

25.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

12.2

upper limit

39.4

Notes
[25] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[26] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fourth secondary endpoint.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Probability to improve by >= 2 steps identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

163

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.0006 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

19.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.6

upper limit

32.1

Notes
[27] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[28] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fourth secondary endpoint.

Secondary: Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	135 ^[29]	135 ^[30]	132 ^[31]
Units: micrometer
arithmetic mean (standard deviation)	-195 ( 146.59 )	-192.4 ( 149.89 )	-66.2 ( 138.99 )

Notes
[29] - FAS with assessment for this end-point.
[30] - FAS with assessment for this end-point.
[31] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

< 0.0001 ^[33]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-157

Confidence interval

level

97.5%

sides

2-sided

lower limit

-190.9

upper limit

-123.1

Notes
[32] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[33] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fifth secondary endpoint.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

< 0.0001 ^[35]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-142.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-179.3

upper limit

-106.3

Notes
[34] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.
[35] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value and the preceding ones were below the significance level of 0.025, the fixed sequence testing did continue with the fifth secondary endpoint.

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF

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End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF

End point 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.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[36]	134 ^[37]	120 ^[38]
Units: scores on a scale
arithmetic mean (standard deviation)	5.73 ( 18.932 )	5.29 ( 19.058 )	3.54 ( 16.768 )

Notes
[36] - FAS with assessment for this end-point.
[37] - FAS with assessment for this end-point.
[38] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.2208 ^[40]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.41

Confidence interval

level

97.5%

sides

2-sided

lower limit

-2.01

upper limit

6.82

Notes
[39] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[40] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value is not below of 0.025, the fixed sequence testing stops here. The sixth secondary endpoint cannot be tested confirmatory.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.5537 ^[42]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.21

Confidence interval

level

97.5%

sides

2-sided

lower limit

-5.79

upper limit

3.37

Notes
[41] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.
[42] - Significance level alpha=0.025 for two sided test to adjust for multiplicity. Since this p-value is not below of 0.025, the fixed sequence testing stops here. The sixth secondary endpoint cannot be tested confirmatory.

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF

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End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF

End point 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.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[43]	134 ^[44]	120 ^[45]
Units: scores on a scale
arithmetic mean (standard deviation)	0.94 ( 16.487 )	5.32 ( 18.475 )	2.26 ( 15.923 )

Notes
[43] - FAS with assessment for this end-point.
[44] - FAS with assessment for this end-point.
[45] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

= 0.5138

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.19

Confidence interval

level

97.5%

sides

2-sided

lower limit

-5.29

upper limit

2.91

Notes
[46] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

Hypothesis: Mean change identical in both groups

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.8498

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

97.5%

sides

2-sided

lower limit

-4.79

upper limit

4.05

Notes
[47] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change from Baseline in BCVA (best corrected visual acuity) as Measured by ETDRS Letter Score at Week 100 - LOCF

Top of page

End point title

Change from Baseline in BCVA (best corrected visual acuity) as Measured by ETDRS Letter Score at Week 100 - LOCF

End point description

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

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[48]	135 ^[49]	132 ^[50]
Units: letters correctly read
arithmetic mean (standard deviation)	11.4 ( 11.2 )	9.4 ( 10.5 )	0.7 ( 11.8 )

Notes
[48] - FAS
[49] - FAS
[50] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

10.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

7.6

upper limit

13.8

Notes
[51] - Stratifying by geographic region (Japan vs non-Japan). LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

8.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

5.2

upper limit

11.3

Notes
[52] - Stratifying by geographic region (Japan vs non-Japan). LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Top of page

End point title

Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

End point description

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

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[53]	135 ^[54]	132 ^[55]
Units: percentage of subjects
number (not applicable)	58.1	49.6	25

Notes
[53] - FAS
[54] - FAS
[55] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

33.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

20.3

upper limit

45.9

Notes
[56] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

24.6

Confidence interval

level

97.5%

sides

2-sided

lower limit

11.9

upper limit

37.3

Notes
[57] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Top of page

End point title

Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

End point description

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

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[58]	135 ^[59]	132 ^[60]
Units: percentage of subjects
number (not applicable)	38.2	31.1	12.1

Notes
[58] - FAS
[59] - FAS
[60] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

26.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

14.8

upper limit

37.5

Notes
[61] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[62]

P-value

= 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

Confidence interval

level

97.5%

sides

2-sided

lower limit

upper limit

29.9

Notes
[62] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects with A >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 100 - LOCF

Top of page

End point title

Percentage of Subjects with A >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 100 - LOCF

End point description

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[63]	135 ^[64]	132 ^[65]
Units: percentage of subjects
number (not applicable)	29.3	32.6	8.2

Notes
[63] - FAS
[64] - FAS
[65] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[66]

P-value

= 0.0004

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

20.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

7.7

upper limit

34.2

Notes
[66] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[67]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

24.4

Confidence interval

level

97.5%

sides

2-sided

lower limit

11.3

upper limit

37.4

Notes
[67] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 100 as Assessed on Optical Coherence Tomography (OCT) - LOCF

Top of page

End point title

Change from Baseline in Central Retinal Thickness (CRT) at Week 100 as Assessed on Optical Coherence Tomography (OCT) - LOCF

End point description

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	135 ^[68]	135 ^[69]	132 ^[70]
Units: micrometer
arithmetic mean (standard deviation)	-211.8 ( 150.9 )	-195.8 ( 141.7 )	-85.7 ( 145.8 )

Notes
[68] - FAS
[69] - FAS
[70] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[71]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-154.4

Confidence interval

level

97.5%

sides

2-sided

lower limit

-189.1

upper limit

-119.7

Notes
[71] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[72]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-126.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-164.6

upper limit

-89

Notes
[72] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 100 - LOCF

Top of page

End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 100 - LOCF

End point 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 sub-scales 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.

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[73]	134 ^[74]	120 ^[75]
Units: scores on a scale
arithmetic mean (standard deviation)	8.2 ( 20.19 )	7 ( 19.28 )	4.8 ( 15.43 )

Notes
[73] - FAS with assessment for this end-point.
[74] - FAS with assessment for this end-point.
[75] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[76]

P-value

= 0.0596

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

3.64

Confidence interval

level

97.5%

sides

2-sided

lower limit

-0.7

upper limit

7.98

Notes
[76] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[77]

P-value

= 0.7144

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.74

Confidence interval

level

97.5%

sides

2-sided

lower limit

-5.25

upper limit

3.78

Notes
[77] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 100 - LOCF

Top of page

End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 100 - LOCF

End point 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.

End point type

Other pre-specified

End point timeframe

Baseline up to Week 100

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[78]	134 ^[79]	120 ^[80]
Units: scores on a scale
arithmetic mean (standard deviation)	4.6 ( 17.62 )	4.9 ( 20.25 )	2.2 ( 16.68 )

Notes
[78] - FAS with assessment for this end-point.
[79] - FAS with assessment for this end-point.
[80] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[81]

P-value

= 0.1792

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.57

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.73

upper limit

6.86

Notes
[81] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[82]

P-value

= 0.5325

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

-6

upper limit

3.39

Notes
[82] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by ETDRS Letter Score at Week 148 - LOCF

Top of page

End point title

Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by ETDRS Letter Score at Week 148 - LOCF

End point description

Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning. During year 3 laser subjects received IAI as needed (PRN).

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[83]	135 ^[84]	132 ^[85]
Units: letters correctly read
arithmetic mean (standard deviation)	10.3 ( 12.5 )	11.7 ( 10.1 )	1.6 ( 12.7 )

Notes
[83] - FAS
[84] - FAS
[85] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[86]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

8.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

5.2

upper limit

12.1

Notes
[86] - Stratifying by geographic region (Japan vs non-Japan). LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[87]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

9.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.5

upper limit

12.9

Notes
[87] - Stratifying by geographic region (Japan vs non-Japan). LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Top of page

End point title

Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

End point description

Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning. During year 3 laser subjects received IAI as needed (PRN).

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[88]	135 ^[89]	132 ^[90]
Units: percentage of subjects
number (not applicable)	55.9	56.3	29.5

Notes
[88] - FAS
[89] - FAS
[90] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[91]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

26.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

13.2

upper limit

39.5

Notes
[91] - Stratifying by geographic region (Japan vs non-Japan). The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[92]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

26.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

13.6

upper limit

39.9

Notes
[92] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Top of page

End point title

Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

End point description

Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning. During year 3 laser subjects received IAI as needed (PRN).

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[93]	135 ^[94]	132 ^[95]
Units: percentage of subjects
number (not applicable)	41.2	42.2	18.9

Notes
[93] - FAS
[94] - FAS
[95] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[96]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

22.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

10.1

upper limit

34.4

Notes
[96] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[97]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

23.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

upper limit

35.5

Notes
[97] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Percentage of Subjects with a >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 148 - LOCF

Top of page

End point title

Percentage of Subjects with a >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 148 - LOCF

End point description

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[98]	135 ^[99]	132 ^[100]
Units: percentage of subjects
number (not applicable)	44.3	47.8	17.4

Notes
[98] - FAS
[99] - FAS
[100] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[101]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

26.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

11.7

upper limit

41.9

Notes
[101] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[102]

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

CMH adjusted difference

Point estimate

30.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

15.4

upper limit

45.1

Notes
[102] - Stratifying by geographic region (Japan vs non-Japan).The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 148 as Assessed On Optical Coherence Tomography (OCT) - LOCF

Top of page

End point title

Change from Baseline in Central Retinal Thickness (CRT) at Week 148 as Assessed On Optical Coherence Tomography (OCT) - LOCF

End point description

During year 3 laser subjects received IAI as needed (PRN).

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	136 ^[103]	135 ^[104]	132 ^[105]
Units: micrometer
arithmetic mean (standard deviation)	-215.2 ( 154.2 )	-202.8 ( 155 )	-122.6 ( 176.2 )

Notes
[103] - FAS
[104] - FAS
[105] - FAS

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

other ^[106]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-124.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

-160.6

upper limit

-88

Notes
[106] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

other ^[107]

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-98.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

-139.4

upper limit

-57.1

Notes
[107] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A negative value indicates a result in favor of EYLEA.

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 148 - LOCF

Top of page

End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 148 - LOCF

End point description

End point type

Other pre-specified

End point timeframe

Baseline up to Week 14

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[108]	134 ^[109]	120 ^[110]
Units: scores on a scale
arithmetic mean (standard deviation)	8.6 ( 20.86 )	9.3 ( 19.94 )	5.3 ( 17.34 )

Notes
[108] - FAS with assessment for this end point.
[109] - FAS with assessment for this end point.
[110] - FAS with assessment for this end point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[111]

P-value

= 0.0862

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

3.56

Confidence interval

level

97.5%

sides

2-sided

lower limit

-1.1

upper limit

8.22

Notes
[111] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[112]

P-value

= 0.7361

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.72

Confidence interval

level

97.5%

sides

2-sided

lower limit

-4.08

upper limit

5.52

Notes
[112] - Treatment group and geographic region (Japan vs. Non-Japan) as factors and baseline value as covariate. LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 148 - LOCF

Top of page

End point title

Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 148 - LOCF

End point 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. During year 3 laser subjects received IAI as needed (PRN).

End point type

Other pre-specified

End point timeframe

Baseline up to Week 148

End point values	Intravitreal Aflibercept Injection 2Q4	Intravitreal Aflibercept Injection 2Q8	Macular Laser Photocoagulation (Control)
Number of subjects analysed	128 ^[113]	134 ^[114]	120 ^[115]
Units: score on a scale
arithmetic mean (standard deviation)	4.4 ( 17.61 )	7.4 ( 21.66 )	3.4 ( 17.19 )

Notes
[113] - FAS with assessment for this end-point.
[114] - FAS with assessment for this end-point.
[115] - FAS with assessment for this end-point.

Intravitreal Aflibercept Injection 2Q4 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q4 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

other ^[116]

P-value

= 0.5337

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.16

Confidence interval

level

97.5%

sides

2-sided

lower limit

-3.02

upper limit

5.34

Notes
[116] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Intravitreal Aflibercept Injection 2Q8 vs. Control

Statistical analysis description

These analysis are not confirmatory.

Comparison groups

Intravitreal Aflibercept Injection 2Q8 v Macular Laser Photocoagulation (Control)

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[117]

P-value

= 0.8323

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.46

Confidence interval

level

97.5%

sides

2-sided

lower limit

-5.34

upper limit

4.42

Notes
[117] - LS mean difference from ANCOVA. The estimate is calculated as EYLEA minus Laser. A positive value indicates a result in favor of EYLEA.

Adverse events

Top of page

Timeframe for reporting adverse events

For each subject from his first study drug injection until 30 days after the last study drug injection at the latest up to termination visit at Week 148

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Intravitreal Aflibercept Injection 2Q4

Reporting group description

Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).

Reporting group title

Macular Laser Photocoagulation (Control)

Reporting group description

Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks. During year 3 laser patients could receive IAI as needed (PRN) .

Reporting group title

Intravitreal Aflibercept Injection 2Q8

Reporting group description

Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8).

Serious adverse events	Intravitreal Aflibercept Injection 2Q4	Macular Laser Photocoagulation (Control)	Intravitreal Aflibercept Injection 2Q8
Total subjects affected by serious adverse events
subjects affected / exposed	63 / 136 (46.32%)	51 / 133 (38.35%)	60 / 135 (44.44%)
number of deaths (all causes)	7	3	7
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adrenal neoplasm
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaplastic astrocytoma
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Bladder neoplasm
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pancreatic carcinoma stage IV
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer stage I
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer stage III
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	2 / 136 (1.47%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Arterial haemorrhage
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 136 (0.74%)	3 / 133 (2.26%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Arteriovenous shunt operation
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract operation
subjects affected / exposed	3 / 136 (2.21%)	2 / 133 (1.50%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteosynthesis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery bypass
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radical prostatectomy
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transurethral prostatectomy
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitrectomy
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Device failure
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injection site injury
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Catheterisation cardiac
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram ST segment depression
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Visual acuity tests abnormal
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain herniation
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	3 / 136 (2.21%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic arthrosis
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 136 (1.47%)	3 / 133 (2.26%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 1	0 / 0
Angina unstable
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bundle branch block right
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 136 (0.74%)	2 / 133 (1.50%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cardiac failure acute
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac sarcoidosis
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac valve disease
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 136 (1.47%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	2 / 136 (1.47%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve stenosis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	4 / 136 (2.94%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	1 / 4	0 / 1	1 / 1
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Ventricular tachycardia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain stem infarction
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cauda equina syndrome
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral atrophy
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 136 (2.94%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	2 / 136 (1.47%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nerve compression
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	5 / 136 (3.68%)	2 / 133 (1.50%)	7 / 135 (5.19%)
occurrences causally related to treatment / all	1 / 8	0 / 2	2 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract subcapsular
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic retinopathy
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iridocyclitis
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular hole
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Optic atrophy
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Posterior capsule opacification
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal artery occlusion
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal exudates
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal neovascularisation
subjects affected / exposed	1 / 136 (0.74%)	3 / 133 (2.26%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal vascular disorder
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinopathy proliferative
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	4 / 136 (2.94%)	2 / 133 (1.50%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reflux gastritis
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermal cyst
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	1 / 136 (0.74%)	2 / 133 (1.50%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress urinary incontinence
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Toxic nodular goitre
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metatarsalgia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal disorder
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 136 (1.47%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tenosynovitis stenosans
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endophthalmitis
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pilonidal cyst
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	3 / 135 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 136 (0.00%)	2 / 133 (1.50%)	2 / 135 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 136 (0.00%)	1 / 133 (0.75%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	0 / 136 (0.00%)	0 / 133 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 136 (0.74%)	0 / 133 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Intravitreal Aflibercept Injection 2Q4	Macular Laser Photocoagulation (Control)	Intravitreal Aflibercept Injection 2Q8
Total subjects affected by non serious adverse events
subjects affected / exposed	117 / 136 (86.03%)	113 / 133 (84.96%)	122 / 135 (90.37%)
Investigations
Blood creatinine increased
subjects affected / exposed	7 / 136 (5.15%)	5 / 133 (3.76%)	6 / 135 (4.44%)
occurrences all number	8	5	6
Blood glucose increased
subjects affected / exposed	10 / 136 (7.35%)	8 / 133 (6.02%)	7 / 135 (5.19%)
occurrences all number	13	10	8
Blood urea increased
subjects affected / exposed	6 / 136 (4.41%)	6 / 133 (4.51%)	10 / 135 (7.41%)
occurrences all number	8	7	10
Glycosylated haemoglobin increased
subjects affected / exposed	12 / 136 (8.82%)	11 / 133 (8.27%)	11 / 135 (8.15%)
occurrences all number	15	11	12
Intraocular pressure increased
subjects affected / exposed	28 / 136 (20.59%)	16 / 133 (12.03%)	18 / 135 (13.33%)
occurrences all number	77	32	51
Visual acuity tests abnormal
subjects affected / exposed	19 / 136 (13.97%)	32 / 133 (24.06%)	22 / 135 (16.30%)
occurrences all number	35	49	63
Vascular disorders
Hypertension
subjects affected / exposed	23 / 136 (16.91%)	24 / 133 (18.05%)	25 / 135 (18.52%)
occurrences all number	32	41	37
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 136 (4.41%)	8 / 133 (6.02%)	3 / 135 (2.22%)
occurrences all number	6	8	3
Eye disorders
Cataract
subjects affected / exposed	31 / 136 (22.79%)	17 / 133 (12.78%)	26 / 135 (19.26%)
occurrences all number	43	29	37
Cataract cortical
subjects affected / exposed	7 / 136 (5.15%)	1 / 133 (0.75%)	6 / 135 (4.44%)
occurrences all number	12	3	7
Conjunctival haemorrhage
subjects affected / exposed	43 / 136 (31.62%)	17 / 133 (12.78%)	39 / 135 (28.89%)
occurrences all number	59	26	58
Cataract subcapsular
subjects affected / exposed	11 / 136 (8.09%)	4 / 133 (3.01%)	5 / 135 (3.70%)
occurrences all number	16	4	6
Conjunctival hyperaemia
subjects affected / exposed	8 / 136 (5.88%)	9 / 133 (6.77%)	3 / 135 (2.22%)
occurrences all number	10	15	5
Corneal erosion
subjects affected / exposed	9 / 136 (6.62%)	7 / 133 (5.26%)	8 / 135 (5.93%)
occurrences all number	11	16	10
Cystoid macular oedema
subjects affected / exposed	10 / 136 (7.35%)	18 / 133 (13.53%)	20 / 135 (14.81%)
occurrences all number	18	51	67
Diabetic retinal oedema
subjects affected / exposed	33 / 136 (24.26%)	18 / 133 (13.53%)	23 / 135 (17.04%)
occurrences all number	49	25	44
Dry eye
subjects affected / exposed	5 / 136 (3.68%)	8 / 133 (6.02%)	5 / 135 (3.70%)
occurrences all number	9	13	7
Eye pain
subjects affected / exposed	15 / 136 (11.03%)	10 / 133 (7.52%)	10 / 135 (7.41%)
occurrences all number	34	15	19
Macular fibrosis
subjects affected / exposed	10 / 136 (7.35%)	11 / 133 (8.27%)	12 / 135 (8.89%)
occurrences all number	13	14	17
Macular oedema
subjects affected / exposed	21 / 136 (15.44%)	22 / 133 (16.54%)	20 / 135 (14.81%)
occurrences all number	41	46	31
Ocular hyperaemia
subjects affected / exposed	5 / 136 (3.68%)	4 / 133 (3.01%)	7 / 135 (5.19%)
occurrences all number	12	5	9
Ocular hypertension
subjects affected / exposed	10 / 136 (7.35%)	6 / 133 (4.51%)	4 / 135 (2.96%)
occurrences all number	21	7	9
Posterior capsule opacification
subjects affected / exposed	10 / 136 (7.35%)	10 / 133 (7.52%)	12 / 135 (8.89%)
occurrences all number	15	18	15
Punctate keratitis
subjects affected / exposed	7 / 136 (5.15%)	8 / 133 (6.02%)	11 / 135 (8.15%)
occurrences all number	13	14	19
Retinal aneurysm
subjects affected / exposed	14 / 136 (10.29%)	9 / 133 (6.77%)	12 / 135 (8.89%)
occurrences all number	26	16	26
Retinal exudates
subjects affected / exposed	20 / 136 (14.71%)	15 / 133 (11.28%)	22 / 135 (16.30%)
occurrences all number	38	32	49
Retinal haemorrhage
subjects affected / exposed	21 / 136 (15.44%)	21 / 133 (15.79%)	25 / 135 (18.52%)
occurrences all number	35	63	64
Retinal vascular disorder
subjects affected / exposed	9 / 136 (6.62%)	5 / 133 (3.76%)	8 / 135 (5.93%)
occurrences all number	20	10	13
Vitreous detachment
subjects affected / exposed	9 / 136 (6.62%)	5 / 133 (3.76%)	10 / 135 (7.41%)
occurrences all number	12	7	11
Visual acuity reduced
subjects affected / exposed	33 / 136 (24.26%)	30 / 133 (22.56%)	33 / 135 (24.44%)
occurrences all number	64	57	81
Vitreous floaters
subjects affected / exposed	13 / 136 (9.56%)	4 / 133 (3.01%)	5 / 135 (3.70%)
occurrences all number	14	4	7
Vitreous haemorrhage
subjects affected / exposed	7 / 136 (5.15%)	8 / 133 (6.02%)	11 / 135 (8.15%)
occurrences all number	14	12	11
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 136 (5.15%)	7 / 133 (5.26%)	6 / 135 (4.44%)
occurrences all number	10	10	6
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 136 (2.94%)	11 / 133 (8.27%)	3 / 135 (2.22%)
occurrences all number	5	11	3
Musculoskeletal pain
subjects affected / exposed	1 / 136 (0.74%)	1 / 133 (0.75%)	9 / 135 (6.67%)
occurrences all number	1	1	9
Infections and infestations
Bronchitis
subjects affected / exposed	12 / 136 (8.82%)	9 / 133 (6.77%)	5 / 135 (3.70%)
occurrences all number	16	10	5
Conjunctivitis
subjects affected / exposed	14 / 136 (10.29%)	8 / 133 (6.02%)	13 / 135 (9.63%)
occurrences all number	16	10	20
Influenza
subjects affected / exposed	7 / 136 (5.15%)	13 / 133 (9.77%)	11 / 135 (8.15%)
occurrences all number	10	16	11
Nasopharyngitis
subjects affected / exposed	38 / 136 (27.94%)	34 / 133 (25.56%)	39 / 135 (28.89%)
occurrences all number	67	62	69
Urinary tract infection
subjects affected / exposed	6 / 136 (4.41%)	6 / 133 (4.51%)	11 / 135 (8.15%)
occurrences all number	8	11	22
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	6 / 136 (4.41%)	9 / 133 (6.77%)	10 / 135 (7.41%)
occurrences all number	6	10	12

More information

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Were there any global substantial amendments to the protocol? Yes

15 Feb 2011

- The guidelines for additional treatment of inadequate responders were revised. - Alternative statistical analysis plans were allowed for the data results according to the regulatory requirements of the governing Health Authority. - The number of initial monthly doses for subjects in the 2Q8 group was changed to 5 (total).

28 May 2013

- The treatment of the fellow eye (non-study eye) was clarified. - The secondary efficacy endpoints were revised. - The statistical methodology section was modified to be consistent with the revisions in the SAP.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/25012934
http://www.ncbi.nlm.nih.gov/pubmed/26198808
http://www.ncbi.nlm.nih.gov/pubmed/26056030

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Clinical trials

Clinical Trial Results: A randomized, double masked, active controlled, phase III study of the efficacy and safety of repeated doses of intravitreal VEGF Trap-Eye in subjects with diabetic macular edema

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF)

Primary: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF)

Secondary: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

Secondary: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

Secondary: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

Secondary: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF

Secondary: Percentage of Subjects 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

Secondary: Percentage of Subjects 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

Secondary: Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF

Secondary: Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF

Secondary: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF

Other pre-specified: Change from Baseline in BCVA (best corrected visual acuity) as Measured by ETDRS Letter Score at Week 100 - LOCF

Other pre-specified: Change from Baseline in BCVA (best corrected visual acuity) as Measured by ETDRS Letter Score at Week 100 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 100 - LOCF

Other pre-specified: Percentage of Subjects with A >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 100 - LOCF

Other pre-specified: Percentage of Subjects with A >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 100 - LOCF

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 100 as Assessed on Optical Coherence Tomography (OCT) - LOCF

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 100 as Assessed on Optical Coherence Tomography (OCT) - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 100 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 100 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 100 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 100 - LOCF

Other pre-specified: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by ETDRS Letter Score at Week 148 - LOCF

Other pre-specified: Change from Baseline in BCVA (Best Corrected Visual Acuity) as Measured by ETDRS Letter Score at Week 148 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Other pre-specified: Percentage of Subjects Who Gained At Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 148 - LOCF

Other pre-specified: Percentage of Subjects with a >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 148 - LOCF

Other pre-specified: Percentage of Subjects with a >=2-Step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 148 - LOCF

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 148 as Assessed On Optical Coherence Tomography (OCT) - LOCF

Other pre-specified: Change from Baseline in Central Retinal Thickness (CRT) at Week 148 as Assessed On Optical Coherence Tomography (OCT) - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 148 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 148 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 148 - LOCF

Other pre-specified: Change From Baseline in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 148 - LOCF

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A randomized, double masked, active controlled, phase III study of the efficacy and safety of repeated doses of intravitreal VEGF Trap-Eye in subjects with diabetic macular edema