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Clinical Trial Results:
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe Nonproliferative Diabetic Retinopathy

Summary
EudraCT number	2016-002639-14
Trial protocol	HU DE GB
Global end of trial date	16 Jul 2019

Results information
Results version number	v1(current)
This version publication date	14 Jul 2020
First version publication date	14 Jul 2020
Other versions

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

VGFTe-OD-1411

ISRCTN number

US NCT number

NCT02718326

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Road, Tarrytown, United States, 10591

Public contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

Scientific contact

Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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

14 Aug 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to assess the efficacy of intravitreal (IVT) aflibercept compared to sham treatment in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The secondary objectives of the study were: - To characterize the safety of IVT aflibercept in subjects with moderately severe to severe NPDR - To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy and reduce the incidence of DME - To determine the anatomic effects of IVT aflibercept in subjects with moderately severe to severe NPDR

Protection of trial subjects

It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Mar 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

Hungary: 10

Country: Number of subjects enrolled

Japan: 11

Country: Number of subjects enrolled

United States: 374

Worldwide total number of subjects

402

EEA total number of subjects

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)

312

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment for this study was conducted in the following countries between 29 Mar 2016 and 07 Aug 2017: Germany, Hungary, Japan, the United Kingdom, and the United States. A total of 759 subjects were screened.

Screening details

Out of 759, 402 subjects were randomized to receive 1 of 3 treatment groups in a 1:1:1 ratio stratified based on their Diabetic Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53). Only 1 eye was selected as the study eye.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor, Carer

Are arms mutually exclusive

Yes

Sham treatment

Arm description

All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

Arm type

Sham injection

Investigational medicinal product name

Sham injection

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Matching sham injections

Intravitreal Aflibercept Injection (IAI) 2Q16

Arm description

All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

Arm type

Experimental

Investigational medicinal product name

Eylea

Investigational medicinal product code

Other name

VEGF Trap-Eye

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

2mg every 16 weeks (2Q16)

Intravitreal Aflibercept Injection (IAI) 2Q8

Arm description

All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

Arm type

Experimental

Investigational medicinal product name

Eylea

Investigational medicinal product code

Other name

VEGF Trap-Eye

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

2 mg every 8 weeks (2Q8); PRN per protocol defined criteria from week 56 through 96

Number of subjects in period 1	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Started	133	135	134
Completed Week 52	109	122	124
Completed Week 100 (End of Study)	97	111	112
Completed	97	111	112
Not completed	36	24	22
Adverse event, serious fatal	8	1	2
Consent withdrawn by subject	4	9	6
Adverse event, non-fatal	4	9	-
Protocol Deviation	1	-	-
Pregnancy	1	-	-
Lost to follow-up	18	5	14

Baseline characteristics

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Reporting group title

Sham treatment

Reporting group description

All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q16

Reporting group description

All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q8

Reporting group description

All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

Reporting group values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8	Total
Number of subjects	133	135	134	402
Age categorical
Units: Subjects
<40 years	11	14	10	35
≥40 - <65 years	94	92	91	277
≥65 years	28	29	33	90
Age Continuous
Units: Years
arithmetic mean (standard deviation)	55.8 ( 10.31 )	55.4 ( 11.13 )	55.8 ( 10.19 )	-
Sex: Female, Male
Units:
Female	64	60	53	177
Male	69	75	81	225
Ethnicity (NIH/OMB)
Units: Subjects
Not Hispanic or Latino	74	97	93	264
Hispanic or Latino	58	37	41	136
Not Reported	1	1	0	2
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	1	4	6
Asian	4	12	7	23
Native Hawaiian or Other Pacific Islander	0	1	1	2
Black or African American	13	16	12	41
White	107	99	104	310
More than one race	0	1	1	2
Not Reported	8	5	5	18
Baseline Diabetic Retinopathy Severity Score (DRSS)
The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
Units: Subjects
Level 47 (Moderately Severe)	99	102	101	302
Level 53 (Severe)	34	33	33	100

Subject analysis set title

IAI 2 mg Groups Combined (2Q16 & 2Q8)

Subject analysis set type

Full analysis

Subject analysis set description

IAI 2Q16: Subjects received a 2mg IAI in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96; IAI 2Q8: Subjects received 2mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

Subject analysis sets values	IAI 2 mg Groups Combined (2Q16 & 2Q8)
Number of subjects	269
Age categorical
Units: Subjects
<40 years	24
≥40 - <65 years	183
≥65 years	62
Age Continuous
Units: Years
arithmetic mean (standard deviation)	55.6 ( 10.66 )
Sex: Female, Male
Units:
Female	113
Male	156
Ethnicity (NIH/OMB)
Units: Subjects
Not Hispanic or Latino	190
Hispanic or Latino	78
Not Reported	1
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	5
Asian	19
Native Hawaiian or Other Pacific Islander	2
Black or African American	28
White	203
More than one race	2
Not Reported	10
Baseline Diabetic Retinopathy Severity Score (DRSS)
The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
Units: Subjects
Level 47 (Moderately Severe)	203
Level 53 (Severe)	66

End points

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Reporting group title

Sham treatment

Reporting group description

All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q16

Reporting group description

All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q8

Reporting group description

All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

Subject analysis set title

IAI 2 mg Groups Combined (2Q16 & 2Q8)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

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End point title

Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

End point description

The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using last observation carried forward (LOCF) method.

End point type

Primary

End point timeframe

At Week 24

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8	IAI 2 mg Groups Combined (2Q16 & 2Q8)
Number of subjects analysed	133	135	134	269
Units: Percentage of subjects
number (not applicable)	6.0	61.5	55.2	58.4

Sham treatment, IAI 2 mg Groups Combined

Comparison groups

Sham treatment v IAI 2 mg Groups Combined (2Q16 & 2Q8)

Number of subjects included in analysis

402

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

52.3

Confidence interval

level

95%

sides

2-sided

lower limit

45.2

upper limit

59.5

Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

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End point title

Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

End point description

The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using LOCF method.

End point type

Primary

End point timeframe

At Week 52

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133	135	134
Units: Percentage of subjects
number (not applicable)	15.0	65.2	79.9

Sham treatment, IAI 2Q16

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

50.1

Confidence interval

level

95%

sides

2-sided

lower limit

40.1

upper limit

60.1

Sham treatment, IAI 2Q18

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

64.8

Confidence interval

level

95%

sides

2-sided

lower limit

55.8

upper limit

73.9

Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

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End point title

Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

End point description

Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of subjects who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (subjects with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).

End point type

Secondary

End point timeframe

At Week 52

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133	135	134
Units: Percentage of subjects
number (not applicable)	20.3	3.7	3.0

Sham treatment, IAI 2Q8

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-17.3

Confidence interval

level

95%

sides

2-sided

lower limit

-24.7

upper limit

-9.9

Sham treatment, IAI 2Q16

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-16.6

Confidence interval

level

95%

sides

2-sided

lower limit

-24.2

upper limit

-9.1

Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

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End point title

Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

End point description

The percentage of subjects who developed CI-DME at week 52 were reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).

End point type

Secondary

End point timeframe

At Week 52

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133	135	134
Units: Percentage of subjects
number (not applicable)	25.6	6.7	8.2

Sham treatment, IAI 2Q8

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-17.3

Confidence interval

level

95%

sides

2-sided

lower limit

-26.2

upper limit

-8.5

Sham treatment, IAI 2Q16

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-18.9

Confidence interval

level

95%

sides

2-sided

lower limit

-27.5

upper limit

-10.4

Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

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End point title

Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

End point description

Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of subjects who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (subjects with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). Subjects who did not have an event were censored at their last visit at or before the week 52 visit. Here, the value "99999" = Not evaluable due to small number of VTC events.

End point type

Secondary

End point timeframe

Baseline through week 52 (day 365)

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133 ^[1]	135 ^[2]	134 ^[3]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (371 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[1] - 99999 = Not evaluable due to small number of VTC events.
[2] - 99999 = Not evaluable due to small number of VTC events.
[3] - 99999 = Not evaluable due to small number of VTC events.

No statistical analyses for this end point

Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

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End point title

Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

End point description

Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized). Subjects who did not have an event were censored at their last visit, at or before the week 52 visit. Here, the value "99999" = Not evaluable due to small number of CI-DME events.

End point type

Secondary

End point timeframe

Baseline through week 52 (day 365)

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133 ^[4]	135 ^[5]	134 ^[6]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (333 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[4] - 99999 = Not evaluable due to small number of CI-DME events
[5] - 99999 = Not evaluable due to small number of CI-DME events
[6] - 99999 = Not evaluable due to small number of CI-DME events

No statistical analyses for this end point

Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

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End point title

Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

End point description

The percentage of subjects who received panretinal photocoagulation (PRP), inclusive of subjects undergoing vitrectomy with endolaser, at week 52 were reported. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).

End point type

Secondary

End point timeframe

At Week 52

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133	135	134
Units: Percentage of subjects
number (not applicable)	6.8	0.7	0.7

Sham treatment, IAI 2Q8

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0096

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.5

upper limit

-1.5

Sham treatment, IAI 2Q16

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0089

Method

Cochran-Mantel-Haenszel

Parameter type

percentage difference

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.5

upper limit

-1.6

Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

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End point title

Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

End point description

The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). AUC was calculated as a weighted average based on total AUC (using the trapezoidal rule) divided by total duration in days. FAS included all randomized subjects who received any study treatment as assigned at baseline (as randomized).

End point type

Secondary

End point timeframe

At week 52

End point values	Sham treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8
Number of subjects analysed	133	135	134
Units: Scores on a scale
arithmetic mean (standard deviation)	0.5 ( 3.01 )	1.7 ( 3.50 )	1.3 ( 3.49 )

Sham treatment, IAI 2Q8

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q8

Number of subjects included in analysis

267

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0529

Method

ANOVA

Parameter type

Estimate for contrast

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

1.6

Sham treatment, IAI 2Q16

Comparison groups

Sham treatment v Intravitreal Aflibercept Injection (IAI) 2Q16

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0057

Method

ANOVA

Parameter type

Estimate for contrast

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

1.94

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AEs) were collected from signature of the informed consent form up to week 100 regardless of seriousness or relationship to investigational product

Adverse event reporting additional description

Reported adverse events are treatment-emergent adverse events (TEAEs) which are AEs that developed/worsened from baseline (day1) up to end of study (week 100).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Sham Treatment

Reporting group description

All subjects received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q16

Reporting group description

All subjects received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96.

Reporting group title

Intravitreal Aflibercept Injection (IAI) 2Q8

Reporting group description

All subjects received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96.

Reporting group title

IAI 2 mg Groups Combined (2Q16 & 2Q8)

Reporting group description

Serious adverse events	Sham Treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8	IAI 2 mg Groups Combined (2Q16 & 2Q8)
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 133 (28.57%)	38 / 135 (28.15%)	47 / 134 (35.07%)	85 / 269 (31.60%)
number of deaths (all causes)	8	1	3	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage 0
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma metastatic
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral ischaemia
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	2 / 134 (1.49%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 133 (1.50%)	1 / 135 (0.74%)	1 / 134 (0.75%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	2 / 133 (1.50%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood glucose increased
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood sodium decreased
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative respiratory failure
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative thoracic procedure complication
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic arthropathy
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocephalus
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic fracture Study Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Coronary artery disease
subjects affected / exposed	1 / 133 (0.75%)	5 / 135 (3.70%)	4 / 134 (2.99%)	9 / 269 (3.35%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 4	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 133 (0.75%)	2 / 135 (1.48%)	3 / 134 (2.24%)	5 / 269 (1.86%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 133 (0.75%)	2 / 135 (1.48%)	1 / 134 (0.75%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 133 (1.50%)	2 / 135 (1.48%)	0 / 134 (0.00%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	1 / 134 (0.75%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 133 (0.00%)	2 / 135 (1.48%)	0 / 134 (0.00%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Cardiac failure chronic
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	2 / 133 (1.50%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 133 (0.00%)	3 / 135 (2.22%)	1 / 134 (0.75%)	4 / 269 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 3	1 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain stem stroke
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemic unconsciousness
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	3 / 133 (2.26%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 133 (0.00%)	2 / 135 (1.48%)	0 / 134 (0.00%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Visual acuity reduced Fellow Eye
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	3 / 134 (2.24%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic retinal oedema Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macular hole Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal vein occlusion Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous adhesions Fellow Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage Fellow Eye
subjects affected / exposed	1 / 133 (0.75%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract Fellow Eye
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iris neovascularisation Fellow Eye
subjects affected / exposed	2 / 133 (1.50%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystoid macular oedema Study Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual acuity reduced Study Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage Study Eye
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic retinopathy Study Eye
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iris neovascularisation Study Eye
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal neovascularisation Study Eye
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diabetic gastroparesis
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	2 / 134 (1.49%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Photosensitivity reaction
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 133 (1.50%)	1 / 135 (0.74%)	3 / 134 (2.24%)	4 / 269 (1.49%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urge incontinence
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 133 (0.75%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 133 (0.75%)	2 / 135 (1.48%)	5 / 134 (3.73%)	7 / 269 (2.60%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 6	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 133 (1.50%)	3 / 135 (2.22%)	3 / 134 (2.24%)	6 / 269 (2.23%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	0 / 133 (0.00%)	3 / 135 (2.22%)	0 / 134 (0.00%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	3 / 134 (2.24%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	2 / 134 (1.49%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	4 / 133 (3.01%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis syndrome
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal osteomyelitis
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal skin infection
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic gangrene
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	3 / 134 (2.24%)	3 / 269 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 133 (0.00%)	2 / 135 (1.48%)	0 / 134 (0.00%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 133 (0.00%)	2 / 135 (1.48%)	0 / 134 (0.00%)	2 / 269 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 133 (0.00%)	1 / 135 (0.74%)	0 / 134 (0.00%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 133 (0.00%)	0 / 135 (0.00%)	1 / 134 (0.75%)	1 / 269 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	1 / 133 (0.75%)	0 / 135 (0.00%)	0 / 134 (0.00%)	0 / 269 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Sham Treatment	Intravitreal Aflibercept Injection (IAI) 2Q16	Intravitreal Aflibercept Injection (IAI) 2Q8	IAI 2 mg Groups Combined (2Q16 & 2Q8)
Total subjects affected by non serious adverse events
subjects affected / exposed	104 / 133 (78.20%)	104 / 135 (77.04%)	106 / 134 (79.10%)	210 / 269 (78.07%)
Investigations
Blood glucose increased
subjects affected / exposed	7 / 133 (5.26%)	3 / 135 (2.22%)	7 / 134 (5.22%)	10 / 269 (3.72%)
occurrences all number	8	3	7	10
Glycosylated haemoglobin increased
subjects affected / exposed	7 / 133 (5.26%)	9 / 135 (6.67%)	9 / 134 (6.72%)	18 / 269 (6.69%)
occurrences all number	7	9	9	18
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	5 / 133 (3.76%)	5 / 135 (3.70%)	8 / 134 (5.97%)	13 / 269 (4.83%)
occurrences all number	5	7	11	18
Vascular disorders
Hypertension
subjects affected / exposed	25 / 133 (18.80%)	28 / 135 (20.74%)	20 / 134 (14.93%)	48 / 269 (17.84%)
occurrences all number	28	32	23	55
Nervous system disorders
Headache
subjects affected / exposed	2 / 133 (1.50%)	7 / 135 (5.19%)	8 / 134 (5.97%)	15 / 269 (5.58%)
occurrences all number	2	9	8	17
Eye disorders
Blepharitis Fellow Eye
subjects affected / exposed	1 / 133 (0.75%)	3 / 135 (2.22%)	7 / 134 (5.22%)	10 / 269 (3.72%)
occurrences all number	1	3	7	10
Cataract Fellow Eye
subjects affected / exposed	4 / 133 (3.01%)	9 / 135 (6.67%)	4 / 134 (2.99%)	13 / 269 (4.83%)
occurrences all number	4	9	4	13
Conjunctival haemorrhage Fellow Eye
subjects affected / exposed	6 / 133 (4.51%)	5 / 135 (3.70%)	8 / 134 (5.97%)	13 / 269 (4.83%)
occurrences all number	7	14	14	28
Diabetic retinal oedema Fellow Eye
subjects affected / exposed	19 / 133 (14.29%)	17 / 135 (12.59%)	23 / 134 (17.16%)	40 / 269 (14.87%)
occurrences all number	25	24	27	51
Diabetic retinopathy Fellow Eye
subjects affected / exposed	12 / 133 (9.02%)	13 / 135 (9.63%)	10 / 134 (7.46%)	23 / 269 (8.55%)
occurrences all number	13	14	10	24
Macular oedema Fellow Eye
subjects affected / exposed	4 / 133 (3.01%)	7 / 135 (5.19%)	6 / 134 (4.48%)	13 / 269 (4.83%)
occurrences all number	4	7	6	13
Retinal exudates Fellow Eye
subjects affected / exposed	8 / 133 (6.02%)	2 / 135 (1.48%)	6 / 134 (4.48%)	8 / 269 (2.97%)
occurrences all number	9	2	7	9
Vitreous haemorrhage Fellow Eye
subjects affected / exposed	4 / 133 (3.01%)	8 / 135 (5.93%)	3 / 134 (2.24%)	11 / 269 (4.09%)
occurrences all number	4	12	3	15
Blepharitis Study Eye
subjects affected / exposed	1 / 133 (0.75%)	2 / 135 (1.48%)	7 / 134 (5.22%)	9 / 269 (3.35%)
occurrences all number	1	2	7	9
Cataract Study Eye
subjects affected / exposed	5 / 133 (3.76%)	8 / 135 (5.93%)	8 / 134 (5.97%)	16 / 269 (5.95%)
occurrences all number	5	8	8	16
Conjunctival haemorrhage Study Eye
subjects affected / exposed	8 / 133 (6.02%)	18 / 135 (13.33%)	25 / 134 (18.66%)	43 / 269 (15.99%)
occurrences all number	14	27	34	61
Diabetic retinal oedema Study Eye
subjects affected / exposed	43 / 133 (32.33%)	14 / 135 (10.37%)	19 / 134 (14.18%)	33 / 269 (12.27%)
occurrences all number	54	22	25	47
Diabetic retinopathy Study Eye
subjects affected / exposed	22 / 133 (16.54%)	3 / 135 (2.22%)	5 / 134 (3.73%)	8 / 269 (2.97%)
occurrences all number	25	4	5	9
Eye pain Study Eye
subjects affected / exposed	6 / 133 (4.51%)	11 / 135 (8.15%)	5 / 134 (3.73%)	16 / 269 (5.95%)
occurrences all number	8	13	5	18
Retinal exudates Study Eye
subjects affected / exposed	6 / 133 (4.51%)	5 / 135 (3.70%)	9 / 134 (6.72%)	14 / 269 (5.20%)
occurrences all number	7	5	9	14
Vitreous detachment Study Eye
subjects affected / exposed	4 / 133 (3.01%)	7 / 135 (5.19%)	7 / 134 (5.22%)	14 / 269 (5.20%)
occurrences all number	4	7	9	16
Vitreous floaters Study Eye
subjects affected / exposed	3 / 133 (2.26%)	7 / 135 (5.19%)	13 / 134 (9.70%)	20 / 269 (7.43%)
occurrences all number	3	8	13	21
Gastrointestinal disorders
Constipation
subjects affected / exposed	3 / 133 (2.26%)	5 / 135 (3.70%)	7 / 134 (5.22%)	12 / 269 (4.46%)
occurrences all number	3	5	7	12
Nausea
subjects affected / exposed	8 / 133 (6.02%)	5 / 135 (3.70%)	6 / 134 (4.48%)	11 / 269 (4.09%)
occurrences all number	9	5	14	19
Infections and infestations
Bronchitis
subjects affected / exposed	7 / 133 (5.26%)	9 / 135 (6.67%)	5 / 134 (3.73%)	14 / 269 (5.20%)
occurrences all number	7	10	5	15
Cellulitis
subjects affected / exposed	6 / 133 (4.51%)	5 / 135 (3.70%)	7 / 134 (5.22%)	12 / 269 (4.46%)
occurrences all number	6	10	7	17
Influenza
subjects affected / exposed	8 / 133 (6.02%)	10 / 135 (7.41%)	4 / 134 (2.99%)	14 / 269 (5.20%)
occurrences all number	8	12	4	16
Nasopharyngitis
subjects affected / exposed	15 / 133 (11.28%)	11 / 135 (8.15%)	11 / 134 (8.21%)	22 / 269 (8.18%)
occurrences all number	16	16	12	28
Urinary tract infection
subjects affected / exposed	16 / 133 (12.03%)	12 / 135 (8.89%)	11 / 134 (8.21%)	23 / 269 (8.55%)
occurrences all number	22	13	13	26
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	13 / 133 (9.77%)	11 / 135 (8.15%)	8 / 134 (5.97%)	19 / 269 (7.06%)
occurrences all number	15	11	8	19

More information

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Were there any global substantial amendments to the protocol? Yes

22 Dec 2015

The purpose of this amendment was to incorporate the following changes and clarifications following discussions with the FDA: The primary outcome measure of the study became the proportion of patients who have improved by ≥2 steps from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score at week 24 in the combined 2Q8 and 2Q16 groups, and at week 52 for each group separately. Secondary endpoints were modified slightly; a few have been separated into 2 endpoints. The 2Q8 group transitioned to a flexible dosing regimen based on the investigator's assessment of DRSS score beginning at week 56.

12 Feb 2016

The purpose of this amendment was to incorporate the following revisions in response to feedback from the Food and Drug Administration (FDA) and the Pharmaceuticals and Medical Devices Agency (PMDA): Revised the significance levels for testing of the secondary efficacy endpoints, per FDA feedback; Added a hemoglobin A1c (HbA1c) assessment at week 24, and fundus photography (FP) at week 8, per PMDA feedback

20 Oct 2016

The purpose of this amendment was to update exclusion criterion #16 to exclude women who were breastfeeding from participation in the study.

24 Jul 2018

The purpose of this amendment was to change the time point for evaluation of the secondary endpoints from week 100 to week 52.

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

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Clinical trials

Clinical Trial Results:
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe Nonproliferative Diabetic Retinopathy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe Nonproliferative Diabetic Retinopathy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

Primary: Percentage of Subjects Who Improved by ≥2 Steps from Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups

Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

Primary: Percentage of Subjects With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline

Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

Secondary: Percentage of Subjects who Developed a Vision-Threatening Complication due to Diabetic Retinopathy at Week 52

Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

Secondary: Percentage of Subjects who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52

Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

Secondary: Time to Development of any Neovascular Vision Threatening Complication (PDR/ASNV) through Week 52

Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

Secondary: Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) through Week 52

Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

Secondary: Percentage of Subjects who Received Panretinal Photocoagulation (PRP), Inclusive of Subjects Undergoing Vitrectomy With Endolaser, at Week 52

Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

Secondary: Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Double-Masked, Randomized Study of the Efficacy and Safety of Intravitreal Aflibercept Injection in Patients with Moderately Severe to Severe Nonproliferative Diabetic Retinopathy