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Trial record 1 of 1 for:    Protocol V, DRCR
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Treatment for CI-DME in Eyes With Very Good VA Study (Protocol V)

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ClinicalTrials.gov Identifier: NCT01909791
Recruitment Status : Completed
First Posted : July 29, 2013
Results First Posted : January 3, 2020
Last Update Posted : July 31, 2020
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
National Eye Institute (NEI)
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Jaeb Center for Health Research

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Outcomes Assessor);   Primary Purpose: Treatment
Condition Diabetic Macular Edema
Interventions Procedure: Prompt Laser
Drug: Prompt aflibercept
Procedure: Deferred laser
Drug: Deferred aflibercept
Enrollment 702
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Period Title: Overall Study
Started 226 240 236
Completed 205 212 208
Not Completed 21 28 28
Reason Not Completed
Death             9             8             4
Withdrawal by Subject             5             9             13
Lost to Follow-up             5             11             10
Missed Visit             2             0             1
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation Total
Hide Arm/Group Description

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Total of all reporting groups
Overall Number of Baseline Participants 226 240 236 702
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
226 240 236 702
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 226 participants 240 participants 236 participants 702 participants
59
(52 to 65)
60
(53 to 66)
60
(53 to 67)
60
(52 to 66)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
Female
95
  42.0%
82
  34.2%
87
  36.9%
264
  37.6%
Male
131
  58.0%
158
  65.8%
149
  63.1%
438
  62.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race/ethnicity Number Analyzed 226 participants 240 participants 236 participants 702 participants
Non-Hispanic White
145
  64.2%
160
  66.7%
161
  68.2%
466
  66.4%
Non-Hispanic Black/African American
37
  16.4%
36
  15.0%
41
  17.4%
114
  16.2%
Hispanic or Latino
31
  13.7%
35
  14.6%
25
  10.6%
91
  13.0%
Asian
6
   2.7%
1
   0.4%
5
   2.1%
12
   1.7%
American Indian or Alaskan Native
1
   0.4%
1
   0.4%
0
   0.0%
2
   0.3%
Native Hawaiian or other Pacific Islander
0
   0.0%
3
   1.3%
1
   0.4%
4
   0.6%
More than one race
4
   1.8%
2
   0.8%
1
   0.4%
7
   1.0%
Unknown or not reported
2
   0.9%
2
   0.8%
2
   0.8%
6
   0.9%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
Canada
1
   0.4%
2
   0.8%
4
   1.7%
7
   1.0%
United States
225
  99.6%
238
  99.2%
232
  98.3%
695
  99.0%
Diabetes type  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
Type 2
211
  93.4%
221
  92.1%
210
  89.0%
642
  91.5%
Type 1
13
   5.8%
18
   7.5%
18
   7.6%
49
   7.0%
Uncertain
2
   0.9%
1
   0.4%
8
   3.4%
11
   1.6%
Duration of diabetes  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 226 participants 240 participants 236 participants 702 participants
15
(10 to 21)
15
(10 to 20)
16
(10 to 24)
15
(10 to 21)
Insulin used  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
161
  71.2%
145
  60.4%
160
  67.8%
466
  66.4%
Hemoglobin A1c   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Hemoglobin A1c percentage
Number Analyzed 217 participants 232 participants 226 participants 675 participants
7.6
(6.8 to 9.1)
7.6
(6.6 to 8.6)
7.6
(6.8 to 8.7)
7.6
(6.7 to 8.8)
[1]
Measure Analysis Population Description: Hemoglobin A1c was missing for 9,8, and 10 eyes in the initiation with aflibercept, initiation with laser photocoagulation, and initiation with observation groups, respectively.
Arterial blood pressure  
Median (Inter-Quartile Range)
Unit of measure:  mmHg
Number Analyzed 226 participants 240 participants 236 participants 702 participants
99
(91 to 107)
98
(89 to 105)
98
(91 to 105)
98
(90 to 106)
Prior myocardial infarction  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
11
   4.9%
21
   8.8%
19
   8.1%
51
   7.3%
Prior stroke  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
16
   7.1%
6
   2.5%
9
   3.8%
31
   4.4%
Body mass index   [1] [2] 
Median (Inter-Quartile Range)
Unit of measure:  Kg/m^2
Number Analyzed 184 participants 207 participants 199 participants 590 participants
32.3
(27.6 to 37.0)
32.1
(28.2 to 37.4)
32.3
(28.0 to 37.5)
32.2
(28.0 to 37.3)
[1]
Measure Description: Calculated as weight in kilograms divided by height in meters squared
[2]
Measure Analysis Population Description: Missing for 42, 33, and 37 participants in the aflibercept, laser and observation groups, respectively.
Daily cigarette smoking  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 226 participants 240 participants 236 participants 702 participants
Never
165
  73.0%
157
  65.4%
141
  59.7%
463
  66.0%
Prior
46
  20.4%
67
  27.9%
75
  31.8%
188
  26.8%
Current
15
   6.6%
16
   6.7%
20
   8.5%
51
   7.3%
Recent or planned diabetic macular edema treatment in non-study eye  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
86
  38.1%
90
  37.5%
92
  39.0%
268
  38.2%
Prior treatment for diabetic macular edema  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
34
  15.0%
31
  12.9%
34
  14.4%
99
  14.1%
Prior anti-VEGF for diabetic macular edema  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
11
   4.9%
14
   5.8%
13
   5.5%
38
   5.4%
Prior focal/grid laser photocoagulation for diabetic macular edema  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
26
  11.5%
24
  10.0%
24
  10.2%
74
  10.5%
Prior panretinal photocoagulation  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
15
   6.6%
12
   5.0%
9
   3.8%
36
   5.1%
Lens status at clinical examination  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
Phakic (natural lens)
180
  79.6%
188
  78.3%
182
  77.1%
550
  78.3%
Prosthetic intraocular lens
46
  20.4%
52
  21.7%
54
  22.9%
152
  21.7%
E-ETDRS visual acuity letter score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
85.2  (3.5) 85.2  (3.8) 85.2  (3.8) 85.2  (3.7)
[1]
Measure Description: Average of screening and randomization values. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Intraocular pressure  
Median (Inter-Quartile Range)
Unit of measure:  mmHg
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
15
(13 to 18)
15
(13 to 18)
15
(13 to 18)
15
(13 to 18)
Patient-reported visual complaints presumed to be from diabetic macular edema  
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
99
  43.8%
116
  48.3%
118
  50.0%
333
  47.4%
Optical coherence tomography machine used to measure central subfield thickness   [1] 
Count of Units
Unit of measure:  Eyes
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
Heidelberg Spectralis
148
  65.5%
151
  62.9%
151
  64.0%
450
  64.1%
Zeiss Cirrus
78
  34.5%
89
  37.1%
85
  36.0%
252
  35.9%
[1]
Measure Description: An optical coherence tomography machine is the device that was used to measure the central subfield thickness.
Central subfield thickness (time-domain equivalent)   [1] 
Mean (Standard Deviation)
Unit of measure:  Microns
Number Analyzed 226 Eyes 240 Eyes 236 Eyes 702 Eyes
306  (55) 314  (52) 314  (64) 311  (57)
[1]
Measure Description: Calculated as the average of screening and randomization values.
Macular volume (time-domain equivalent)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Mm^3
Number Analyzed 226 Eyes 240 Eyes 235 Eyes 701 Eyes [3] 
7.9  (1.1) 8.0  (1.2) 8.0  (1.1) 8.0  (1.0)
[1]
Measure Description: Average of screening and randomization values.
[2]
Measure Analysis Population Description: missing for one participant in the observation group
[3]
701 participants
Diabetic retinopathy severity level   [1] [2] 
Count of Units
Unit of measure:  Eyes
Number Analyzed 216 Eyes 227 Eyes 229 Eyes 672 Eyes
Diabetic Retinopathy absent or questionable
2
   0.9%
4
   1.8%
1
   0.4%
7
   1.0%
Microaneurysms only
13
   6.0%
8
   3.5%
6
   2.6%
27
   4.0%
Mild to moderate NPDR
119
  55.1%
132
  58.1%
142
  62.0%
393
  58.5%
Moderately severe to severe NPDR
58
  26.9%
64
  28.2%
62
  27.1%
184
  27.4%
Inactive PDR
6
   2.8%
7
   3.1%
7
   3.1%
20
   3.0%
Mild to moderate PDR
14
   6.5%
12
   5.3%
9
   3.9%
35
   5.2%
[1]
Measure Description: Graded by a central reading center. PDR, proliferative diabetic retinopathy, NPDR, non-proliferative diabetic retinopathy
[2]
Measure Analysis Population Description: Missing for 10, 13, and 7 eyes in the aflibercept, laser, and observation groups, respectively.
1.Primary Outcome
Title Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Count of Units
Unit of Measure: Eyes
33
  16.1%
36
  17.0%
39
  18.8%
2.Secondary Outcome
Title Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 226 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 226 220
Count of Units
Unit of Measure: Eyes
≥ 5-Letter Increase
61
  29.0%
44
  19.5%
33
  15.0%
≥ 5-Letter Decrease
19
   9.0%
36
  15.9%
25
  11.4%
≥ 10-Letter Decrease
6
   2.9%
9
   4.0%
7
   3.2%
≥ 15-Letter Decrease
3
   1.4%
4
   1.8%
6
   2.7%
3.Secondary Outcome
Title Change in E-ETDRS Visual Acuity Letter Score From Baseline
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 226 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 226 220
Mean (Standard Deviation)
Unit of Measure: units on a scale
2.1  (5.0) 0.1  (5.5) 0.0  (5.4)
4.Secondary Outcome
Title Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve)
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up.
Time Frame 2 year
Hide Outcome Measure Data
Hide Analysis Population Description
Best-corrected visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the early treatment diabetic retinopathy study method . Best value on the scale 100, worst 0.
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Mean (Standard Deviation)
Unit of Measure: units on a scale
1.5  (4.0) 0.0  (3.9) -0.4  (4.2)
5.Secondary Outcome
Title Change in OCT Central Subfield Thickness From Baseline
Hide Description [Not Specified]
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 207
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 207
Mean (Standard Deviation)
Unit of Measure: microns
-48  (65) -41  (75) -42  (75)
6.Secondary Outcome
Title Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
Hide Description Logarithmic transformation of optical coherence tomography central subfield thickness (CST) is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 223 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 223 220
Count of Units
Unit of Measure: Eyes
≥ 2 log-step CST decrease (improvement)
7
   3.3%
11
   4.9%
8
   3.6%
≥ 1 log-step CST decrease (improvement)
56
  26.7%
45
  20.2%
39
  17.7%
≥ 1 log-step CST increase (worsening)
1
   0.5%
12
   5.4%
14
   6.4%
≥ 2 log-step CST increase (worsening)
0
   0.0%
3
   1.3%
3
   1.4%
7.Secondary Outcome
Title Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
Hide Description Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men.
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 223 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 223 220
Count of Units
Unit of Measure: Eyes
93
  44.3%
58
  26.0%
67
  30.5%
8.Secondary Outcome
Title Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
Hide Description [Not Specified]
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 226 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 226 220
Mean (Standard Deviation)
Unit of Measure: Injections
6.0  (2.5) 0.7  (2.1) 1.4  (2.6)
9.Secondary Outcome
Title Number of Eyes With ≥ 2-step Worsening of Diabetic Retinopathy
Hide Description Includes eyes with baseline severity level of 75 (high-risk proliferative diabetic retinopathy) or less based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 185 187 188
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
185 187 188
Count of Units
Unit of Measure: Eyes
7
   3.8%
18
   9.6%
20
  10.6%
10.Secondary Outcome
Title For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment
Hide Description [Not Specified]
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 240 236
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
240 236
Count of Units
Unit of Measure: Eyes
60
  25.0%
80
  33.9%
11.Secondary Outcome
Title Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Count of Units
Unit of Measure: Eyes
≥ 5-Letter Improvement
55
  26.8%
53
  25.0%
43
  20.7%
≥ 10-Letter Worsening
18
   8.8%
14
   6.6%
14
   6.7%
≥ 15-Letter Worsening
5
   2.4%
8
   3.8%
8
   3.8%
12.Secondary Outcome
Title Change in E-ETDRS Visual Acuity Letter Score From Baseline
Hide Description Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initiation With Aflibercept Initiation With Laser Photocoagulation Initiation With Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.9  (6.4) 0.1  (6.3) -0.4  (6.4)
13.Secondary Outcome
Title Change in OCT Central Subfield Thickness From Baseline
Hide Description Measured using spectral-domain optical coherence tomography (OCT).
Time Frame 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 210 223 220
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
210 223 220
Mean (Standard Deviation)
Unit of Measure: microns
-50  (55) -30  (69) -25  (73)
14.Secondary Outcome
Title Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening
Hide Description Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 207
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 207
Count of Units
Unit of Measure: Eyes
≥ 2 log-step CST decrease (improvement)
12
   5.9%
18
   8.5%
13
   6.3%
≥ 1 log-step CST decrease (improvement)
57
  27.8%
56
  26.4%
61
  29.5%
≥ 1 log-step CST increase (worsening)
6
   2.9%
10
   4.7%
11
   5.3%
≥ 2 log-step CST increase (worsening)
1
   0.5%
1
   0.5%
2
   1.0%
15.Secondary Outcome
Title Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease
Hide Description Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis ≥ 305 µm in women and ≥ 320 µm in men, and Zeiss Cirrus ≥ 290 µm in women and ≥ 305 µm in men.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 207
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 207
Count of Units
Unit of Measure: Eyes
95
  46.3%
90
  42.5%
74
  35.7%
16.Secondary Outcome
Title Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant
Hide Description [Not Specified]
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
The initial laser session was completed for all eyes in the initial laser group.
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Mean (Standard Deviation)
Unit of Measure: Focal/grid photocoagulation session
0.1  (0.4) 1.5  (0.9) 0.0  (0.3)
17.Secondary Outcome
Title Number of Eyes With ≥ 2-step Improvement of Diabetic Retinopathy
Hide Description Includes eyes with baseline severity level of 35 (mild non-proliferative diabetic retinopathy) or greater based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. Excludes eyes with severity level 60 at baseline since improvement is not possible in these eyes.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 165 170 177
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
165 170 177
Count of Units
Unit of Measure: Eyes
23
  13.9%
21
  12.4%
18
  10.2%
18.Secondary Outcome
Title Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant
Hide Description [Not Specified]
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Initial Aflibercept Initial Laser With Deferred Aflibercept if Needed Observation
Hide Arm/Group Description:

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Overall Number of Participants Analyzed 205 212 208
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
205 212 208
Mean (Standard Deviation)
Unit of Measure: Injections
8.3  (4.2) 2.1  (4.0) 3.1  (4.9)
Time Frame 2 Years
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Initiation With Laser Photocoagulation Initiation With Observation Initiation With Aflibercept
Hide Arm/Group Description

Focal/grid laser followed by intravitreal aflibercept if vision worsens

Prompt Laser: Focal/grid laser performed at baseline and as needed during follow-up

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

No treatment to start followed by intravitreal aflibercept if vision worsens (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Intravitreal aflibercept at baseline and every 4 weeks as needed (deferred laser may be added to intravitreal aflibercept if certain criteria are met)

Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Deferred laser: Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

All-Cause Mortality
Initiation With Laser Photocoagulation Initiation With Observation Initiation With Aflibercept
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/226 (4.42%)      9/240 (3.75%)      5/236 (2.12%)    
Hide Serious Adverse Events
Initiation With Laser Photocoagulation Initiation With Observation Initiation With Aflibercept
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   64/240 (26.67%)      77/236 (32.63%)      69/226 (30.53%)    
Blood and lymphatic system disorders       
Anaemia * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 1/226 (0.44%)  1
Anaemia of chronic disease * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Lymphoma * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Plasma cell myeloma * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Cardiac disorders       
Acute coronary syndrome * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Acute myocardial infarction * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Angina pectoris * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Arrhythmia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Arteriosclerosis coronary artery * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Atrial fibrillation * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 2/226 (0.88%)  2
Atrioventricular block first degree * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Bicuspid aortic valve * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Bradycardia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Cardiac arrest * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Cardiac failure * 1  1/240 (0.42%)  3 0/236 (0.00%)  0 1/226 (0.44%)  1
Cardiac failure congestive * 1  4/240 (1.67%)  6 5/236 (2.12%)  5 5/226 (2.21%)  5
Cardiomyopathy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Coronary artery disease * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 0/226 (0.00%)  0
Coronary artery stenosis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hypertensive heart disease * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Myocardial infarction * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 5/226 (2.21%)  5
Endocrine disorders       
Diabetes mellitus inadequate control * 1  0/240 (0.00%)  0 2/236 (0.85%)  3 2/226 (0.88%)  2
Diabetic coma * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Diabetic ketoacidosis * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 0/226 (0.00%)  0
Hyperglycaemia * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Hypoglycaemia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 2/226 (0.88%)  2
Thyroid cancer * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Eye disorders       
Cataract traumatic * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Rhegmatogenous retinal detachment * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Vitreous haemorrhage * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain * 1  3/240 (1.25%)  3 0/236 (0.00%)  0 0/226 (0.00%)  0
Appendicitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Ascites * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Colitis ischaemic * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Diverticulum * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Dysphagia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Food poisoning * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Gastroenteritis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Hiatus hernia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Intestinal obstruction * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Large intestine polyp * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Nausea * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Pancreatitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
General disorders       
Chest discomfort * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Chest pain * 1  4/240 (1.67%)  4 6/236 (2.54%)  7 3/226 (1.33%)  3
Death * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 3/226 (1.33%)  3
Fatigue * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Flank pain * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hernia * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 0/226 (0.00%)  0
Multi-organ failure * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Oedema peripheral * 1  3/240 (1.25%)  4 0/236 (0.00%)  0 0/226 (0.00%)  0
Peripheral swelling * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Hepatobiliary disorders       
Cholecystitis acute * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 0/226 (0.00%)  0
Cholelithiasis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Hepatic cirrhosis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Liver abscess * 1  0/240 (0.00%)  0 1/236 (0.42%)  2 0/226 (0.00%)  0
Immune system disorders       
Drug hypersensitivity * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hypersensitivity * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Infections and infestations       
Abscess * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Bronchopneumonia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Infection * 1  4/240 (1.67%)  4 0/236 (0.00%)  0 2/226 (0.88%)  2
Influenza * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Localised infection * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Sepsis * 1  2/240 (0.83%)  2 2/236 (0.85%)  2 1/226 (0.44%)  1
Staphylococcal infection * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Injury, poisoning and procedural complications       
Back injury * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Compression fracture * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Fall * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Fibula fracture * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Heat exhaustion * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Ligament rupture * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Spinal fracture * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Wound * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Investigations       
Blood creatinine abnormal * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Blood electrolytes decreased * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Blood glucose decreased * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Blood glucose increased * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Blood potassium increased * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Troponin increased * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 3/226 (1.33%)  3
Metabolism and nutrition disorders       
Dehydration * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 0/226 (0.00%)  0
Fluid overload * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hypercalcaemia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Hyperkalaemia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hypomagnesaemia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Back pain * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hip fracture * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Lower limb fracture * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Multiple fractures * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Myalgia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Osteoarthritis * 1  4/240 (1.67%)  4 0/236 (0.00%)  0 1/226 (0.44%)  1
Osteomyelitis * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 1/226 (0.44%)  1
Pain in extremity * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Rhabdomyolysis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Rib fracture * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Vertebral foraminal stenosis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasm malignant * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Nervous system disorders       
Aphasia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Carotid artery occlusion * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Concussion * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Convulsion * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Haemorrhage intracranial * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hypoglycaemic encephalopathy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Seizure * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Syncope * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Pregnancy, puerperium and perinatal conditions       
Pregnancy * 1  0/240 (0.00%)  0 1/236 (0.42%)  2 0/226 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury * 1  2/240 (0.83%)  2 3/236 (1.27%)  3 0/226 (0.00%)  0
Cardiorenal syndrome * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Chronic kidney disease * 1  1/240 (0.42%)  2 1/236 (0.42%)  1 2/226 (0.88%)  2
Cystitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
End stage renal disease * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Kidney infection * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Nephrolithiasis * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Nephropathy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Nephrotic syndrome * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Pyelonephritis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Renal failure * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 3/226 (1.33%)  3
Renal failure acute * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 0/226 (0.00%)  0
Renal failure chronic * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Renal impairment * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Urinary tract infection * 1  4/240 (1.67%)  4 1/236 (0.42%)  1 1/226 (0.44%)  1
Reproductive system and breast disorders       
Breast cancer * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Menorrhagia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 0/226 (0.00%)  0
Asthma * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Dyspnoea * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 2/226 (0.88%)  2
Epistaxis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Lung neoplasm malignant * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  2
Pleural effusion * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Pneumonia * 1  4/240 (1.67%)  4 3/236 (1.27%)  3 4/226 (1.77%)  4
Pulmonary embolism * 1  3/240 (1.25%)  3 0/236 (0.00%)  0 1/226 (0.44%)  1
Pulmonary hypertension * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Respiratory distress * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Skin and subcutaneous tissue disorders       
Cellulitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 6/226 (2.65%)  7
Diabetic foot * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 1/226 (0.44%)  1
Diabetic ulcer * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Gangrene * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Herpes zoster * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Skin ulcer * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Surgical and medical procedures       
Abdominal hernia repair * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Cardiac operation * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Cardiac pacemaker insertion * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Carpal tunnel decompression * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Cholecystectomy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Coronary arterial stent insertion * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Coronary artery bypass * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Gastric banding * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Gastric bypass * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hysterectomy * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Implantable defibrillator insertion * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Knee arthroplasty * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 3/226 (1.33%)  3
Knee operation * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 3/226 (1.33%)  3
Leg amputation * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Stent placement * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 0/226 (0.00%)  0
Surgery * 1  3/240 (1.25%)  3 1/236 (0.42%)  1 0/226 (0.00%)  0
Toe amputation * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Vascular graft * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Vascular disorders       
Aortic stenosis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Arteriovenous fistula * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Carotid artery disease * 1  3/240 (1.25%)  3 1/236 (0.42%)  1 0/226 (0.00%)  0
Cerebral haemorrhage * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Cerebrovascular accident * 1  5/240 (2.08%)  5 3/236 (1.27%)  3 3/226 (1.33%)  3
Embolism * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Haematoma * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Haemorrhagic stroke * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Hypertension * 1  2/240 (0.83%)  2 3/236 (1.27%)  3 0/226 (0.00%)  0
Hypotension * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Ischaemic stroke * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Orthostatic hypotension * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Peripheral arterial occlusive disease * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Poor peripheral circulation * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Transient ischaemic attack * 1  3/240 (1.25%)  3 1/236 (0.42%)  1 0/226 (0.00%)  0
1
Term from vocabulary, MedDRA (Unspecified)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Initiation With Laser Photocoagulation Initiation With Observation Initiation With Aflibercept
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   194/240 (80.83%)      197/236 (83.47%)      185/226 (81.86%)    
Blood and lymphatic system disorders       
Anaemia * 1  6/240 (2.50%)  6 9/236 (3.81%)  9 4/226 (1.77%)  4
Anaemia of chronic disease * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Leukocytosis * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 1/226 (0.44%)  1
Lymphadenopathy * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Lymphoedema * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Thrombocytopenia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Cardiac disorders       
Angina pectoris * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Arrhythmia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Arteriosclerosis coronary artery * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Atrial fibrillation * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 3/226 (1.33%)  3
Atrial flutter * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 3/226 (1.33%)  3
Atrioventricular block first degree * 1  2/240 (0.83%)  3 0/236 (0.00%)  0 0/226 (0.00%)  0
Bradycardia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Cardiac arrest * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Cardiac failure * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Cardiac failure congestive * 1  5/240 (2.08%)  6 1/236 (0.42%)  1 1/226 (0.44%)  1
Coronary artery disease * 1  2/240 (0.83%)  2 4/236 (1.69%)  4 1/226 (0.44%)  1
Coronary artery stenosis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Ischaemic cardiomyopathy * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Long QT syndrome * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Palpitations * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Tachycardia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 3/226 (1.33%)  3
Ventricular tachycardia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Ear and labyrinth disorders       
Deafness * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Ear infection * 1  4/240 (1.67%)  4 5/236 (2.12%)  5 4/226 (1.77%)  4
Ear pain * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Mastoiditis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Meniere's disease * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Otitis externa * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Tinnitus * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Tympanic membrane perforation * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Endocrine disorders       
Autoimmune thyroiditis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Diabetes mellitus * 1  9/240 (3.75%)  11 8/236 (3.39%)  8 4/226 (1.77%)  5
Diabetes mellitus inadequate control * 1  9/240 (3.75%)  10 7/236 (2.97%)  8 7/226 (3.10%)  7
Diabetic ketoacidosis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Goitre * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Hyperglycaemia * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 2/226 (0.88%)  2
Hyperparathyroidism * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 0/226 (0.00%)  0
Hyperthyroidism * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Hypoglycaemia * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 4/226 (1.77%)  6
Hypothyroidism * 1  0/240 (0.00%)  0 6/236 (2.54%)  6 2/226 (0.88%)  2
Pituitary tumour benign * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Thyroid neoplasm * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 3/226 (1.33%)  3
Eye disorders       
Age-related macular degeneration * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Altered visual depth perception * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Amaurosis fugax * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Angle closure glaucoma * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Asthenopia * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Blepharitis * 1  2/240 (0.83%)  3 3/236 (1.27%)  3 1/226 (0.44%)  1
Blepharospasm * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Borderline glaucoma * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Cataract * 1  14/240 (5.83%)  14 14/236 (5.93%)  15 17/226 (7.52%)  17
Cataract cortical * 1  6/240 (2.50%)  6 6/236 (2.54%)  6 11/226 (4.87%)  11
Cataract nuclear * 1  4/240 (1.67%)  4 1/236 (0.42%)  1 8/226 (3.54%)  8
Cataract subcapsular * 1  4/240 (1.67%)  4 4/236 (1.69%)  6 11/226 (4.87%)  13
Chalazion * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 1/226 (0.44%)  1
Choroidal neovascularisation * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Conjunctival haemorrhage * 1  8/240 (3.33%)  11 9/236 (3.81%)  13 17/226 (7.52%)  23
Conjunctival hyperaemia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Conjunctivitis * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 2/226 (0.88%)  2
Conjunctivitis allergic * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 2/226 (0.88%)  2
Conjunctivitis viral * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 1/226 (0.44%)  1
Corneal abrasion * 1  2/240 (0.83%)  2 2/236 (0.85%)  3 3/226 (1.33%)  4
Corneal defect * 1  1/240 (0.42%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Corneal disorder * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Corneal dystrophy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Corneal erosion * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Corneal oedema * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Corneal opacity * 1  1/240 (0.42%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Corneal pigmentation * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Corneal scar * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Cystoid macular oedema * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Diabetic retinal oedema * 1  6/240 (2.50%)  6 7/236 (2.97%)  7 2/226 (0.88%)  2
Diabetic retinopathy * 1  6/240 (2.50%)  7 2/236 (0.85%)  2 5/226 (2.21%)  5
Diplopia * 1  8/240 (3.33%)  8 2/236 (0.85%)  2 1/226 (0.44%)  1
Dry eye * 1  11/240 (4.58%)  12 8/236 (3.39%)  10 17/226 (7.52%)  18
Eye discharge * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 1/226 (0.44%)  1
Eye irritation * 1  6/240 (2.50%)  6 7/236 (2.97%)  7 12/226 (5.31%)  13
Eye pain * 1  5/240 (2.08%)  8 11/236 (4.66%)  14 16/226 (7.08%)  19
Eye pruritus * 1  9/240 (3.75%)  10 3/236 (1.27%)  3 6/226 (2.65%)  6
Eye swelling * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Eyelid margin crusting * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Eyelid oedema * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Eyelid pain * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Eyelid ptosis * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Foreign body in eye * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Foreign body sensation in eyes * 1  2/240 (0.83%)  3 3/236 (1.27%)  3 2/226 (0.88%)  2
Glare * 1  6/240 (2.50%)  6 1/236 (0.42%)  1 0/226 (0.00%)  0
Hordeolum * 1  5/240 (2.08%)  5 2/236 (0.85%)  2 1/226 (0.44%)  2
Hyalosis asteroid * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hyphaema * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Iris adhesions * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Iris neovascularisation * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Iritis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 2/226 (0.88%)  2
Keratitis * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Keratopathy * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Lacrimation increased * 1  9/240 (3.75%)  9 8/236 (3.39%)  10 8/226 (3.54%)  8
Macular degeneration * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Macular fibrosis * 1  10/240 (4.17%)  10 1/236 (0.42%)  1 6/226 (2.65%)  7
Macular ischaemia * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 0/226 (0.00%)  0
Macular oedema * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 0/226 (0.00%)  0
Meibomian gland dysfunction * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Metamorphopsia * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 3/226 (1.33%)  4
Ocular discomfort * 1  3/240 (1.25%)  3 3/236 (1.27%)  4 7/226 (3.10%)  7
Ocular hyperaemia * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 6/226 (2.65%)  6
Ocular hypertension * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Ophthalmic herpes simplex * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Optic atrophy * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Optic ischaemic neuropathy * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Optic nerve cupping * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Photophobia * 1  4/240 (1.67%)  4 7/236 (2.97%)  8 8/226 (3.54%)  8
Photopsia * 1  3/240 (1.25%)  3 4/236 (1.69%)  4 7/226 (3.10%)  7
Posterior capsule opacification * 1  3/240 (1.25%)  3 1/236 (0.42%)  1 2/226 (0.88%)  2
Punctate keratitis * 1  3/240 (1.25%)  3 2/236 (0.85%)  3 4/226 (1.77%)  4
Retinal aneurysm * 1  3/240 (1.25%)  3 5/236 (2.12%)  5 3/226 (1.33%)  3
Retinal artery embolism * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Retinal detachment * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Retinal exudates * 1  5/240 (2.08%)  6 12/236 (5.08%)  12 7/226 (3.10%)  7
Retinal haemorrhage * 1  2/240 (0.83%)  2 10/236 (4.24%)  11 4/226 (1.77%)  4
Retinal ischaemia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Retinal neovascularisation * 1  5/240 (2.08%)  5 3/236 (1.27%)  3 2/226 (0.88%)  3
Retinal oedema * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Retinal pigment epitheliopathy * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Retinal tear * 1  2/240 (0.83%)  2 2/236 (0.85%)  2 1/226 (0.44%)  1
Retinal vein occlusion * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Retinopathy * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 1/226 (0.44%)  1
Retinopathy hypertensive * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Rhegmatogenous retinal detachment * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Subretinal fibrosis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Ulcerative keratitis * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Vision blurred * 1  31/240 (12.92%)  39 34/236 (14.41%)  43 40/226 (17.70%)  46
Visual acuity reduced * 1  15/240 (6.25%)  16 16/236 (6.78%)  16 6/226 (2.65%)  6
Visual field defect * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Visual impairment * 1  11/240 (4.58%)  12 11/236 (4.66%)  13 9/226 (3.98%)  11
Vitreous adhesions * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 2/226 (0.88%)  2
Vitreous detachment * 1  3/240 (1.25%)  3 4/236 (1.69%)  4 12/226 (5.31%)  12
Vitreous disorder * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Vitreous floaters * 1  16/240 (6.67%)  16 21/236 (8.90%)  22 27/226 (11.95%)  34
Vitreous haemorrhage * 1  6/240 (2.50%)  7 5/236 (2.12%)  5 8/226 (3.54%)  11
Gastrointestinal disorders       
Abdominal discomfort * 1  2/240 (0.83%)  2 1/236 (0.42%)  1 2/226 (0.88%)  2
Abdominal distension * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Abdominal pain * 1  1/240 (0.42%)  2 1/236 (0.42%)  1 2/226 (0.88%)  2
Abdominal pain upper * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 1/226 (0.44%)  1
Anal incontinence * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Appendicitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Chronic gastritis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Colon adenoma * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Colon cancer * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Constipation * 1  4/240 (1.67%)  4 3/236 (1.27%)  4 1/226 (0.44%)  1
Dental caries * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Diabetic gastroparesis * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 1/226 (0.44%)  1
Diarrhoea * 1  6/240 (2.50%)  6 6/236 (2.54%)  6 8/226 (3.54%)  9
Diverticulum * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Dyspepsia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Food poisoning * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 2/226 (0.88%)  2
Gastroenteritis * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 2/226 (0.88%)  2
Gastroenteritis viral * 1  2/240 (0.83%)  2 3/236 (1.27%)  3 2/226 (0.88%)  2
Gastrointestinal haemorrhage * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Gastrooesophageal reflux disease * 1  5/240 (2.08%)  5 6/236 (2.54%)  6 7/226 (3.10%)  7
Gingival pain * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Haematochezia * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Haemorrhoids * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Hiatus hernia * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Impaired gastric emptying * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Irritable bowel syndrome * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Large intestine polyp * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 3/226 (1.33%)  3
Nausea * 1  11/240 (4.58%)  12 8/236 (3.39%)  9 7/226 (3.10%)  8
Pancreatitis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Rectal haemorrhage * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Salivary gland disorder * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Tooth abscess * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 4/226 (1.77%)  4
Tooth fracture * 1  3/240 (1.25%)  3 0/236 (0.00%)  0 3/226 (1.33%)  3
Tooth infection * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 4/226 (1.77%)  5
Tooth loss * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Toothache * 1  2/240 (0.83%)  3 0/236 (0.00%)  0 6/226 (2.65%)  7
Vomiting * 1  6/240 (2.50%)  6 4/236 (1.69%)  4 7/226 (3.10%)  8
General disorders       
Chest discomfort * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 1/226 (0.44%)  1
Chest pain * 1  4/240 (1.67%)  4 7/236 (2.97%)  7 3/226 (1.33%)  4
Chills * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Cyst * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Fatigue * 1  3/240 (1.25%)  3 4/236 (1.69%)  4 5/226 (2.21%)  5
Flank pain * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Hernia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Injection site discomfort * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Injection site irritation * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Lethargy * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 0/226 (0.00%)  0
Local swelling * 1  0/240 (0.00%)  0 1/236 (0.42%)  2 0/226 (0.00%)  0
Necrosis * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Oedema peripheral * 1  8/240 (3.33%)  10 8/236 (3.39%)  8 3/226 (1.33%)  3
Pain * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 4/226 (1.77%)  5
Peripheral swelling * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 2/226 (0.88%)  2
Pyrexia * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 6/226 (2.65%)  6
Swelling * 1  2/240 (0.83%)  2 3/236 (1.27%)  3 4/226 (1.77%)  4
Systemic inflammatory response syndrome * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Hepatobiliary disorders       
Cholangitis * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Cholelithiasis * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 2/226 (0.88%)  2
Hepatic cirrhosis * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 0/226 (0.00%)  0
Jaundice * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Non-alcoholic steatohepatitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Immune system disorders       
Hypersensitivity * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 2/226 (0.88%)  2
Seasonal allergy * 1  7/240 (2.92%)  7 2/236 (0.85%)  2 6/226 (2.65%)  6
Systemic lupus erythematosus * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Urticaria * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 0/226 (0.00%)  0
Infections and infestations       
Abscess * 1  0/240 (0.00%)  0 3/236 (1.27%)  3 0/226 (0.00%)  0
Bronchopneumonia * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 2/226 (0.88%)  2
Candida infection * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 0/226 (0.00%)  0
Diverticulitis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 2/226 (0.88%)  2
Escherichia infection * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Fungal infection * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 2/226 (0.88%)  2
Fungal skin infection * 1  0/240 (0.00%)  0 2/236 (0.85%)  2 1/226 (0.44%)  1
Helicobacter infection * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 1/226 (0.44%)  1
Infection * 1  4/240 (1.67%)  4 2/236 (0.85%)  2 2/226 (0.88%)  2
Influenza * 1  7/240 (2.92%)  7 9/236 (3.81%)  10 10/226 (4.42%)  11
Localised infection * 1  3/240 (1.25%)  3 2/236 (0.85%)  2 8/226 (3.54%)  10
Onychomycosis * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 1/226 (0.44%)  1
Oral herpes * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Respiratory tract infection fungal * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 0/226 (0.00%)  0
Sepsis * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 2/226 (0.88%)  2
Staphylococcal infection * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 3/226 (1.33%)  4
Streptococcal infection * 1  2/240 (0.83%)  2 0/236 (0.00%)  0 0/226 (0.00%)  0
Injury, poisoning and procedural complications       
Accidental overdose * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Animal bite * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 2/226 (0.88%)  2
Arthropod bite * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 5/226 (2.21%)  5
Arthropod sting * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Chemical injury * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Fall * 1  5/240 (2.08%)  5 5/236 (2.12%)  8 4/226 (1.77%)  4
Head injury * 1  1/240 (0.42%)  1 1/236 (0.42%)  1 0/226 (0.00%)  0
Injury * 1  1/240 (0.42%)  1 2/236 (0.85%)  2 0/226 (0.00%)  0
Joint injury * 1  1/240 (0.42%)  2 2/236 (0.85%)  2 1/226 (0.44%)  1
Laceration * 1  3/240 (1.25%)  3 1/236 (0.42%)  1 4/226 (1.77%)  4
Ligament rupture * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Limb injury * 1  4/240 (1.67%)  4 2/236 (0.85%)  2 1/226 (0.44%)  1
Limb traumatic amputation * 1  0/240 (0.00%)  0 0/236 (0.00%)  0 1/226 (0.44%)  1
Road traffic accident * 1  1/240 (0.42%)  1 3/236 (1.27%)  3 2/226 (0.88%)  2
Spinal fracture * 1  0/240 (0.00%)  0 1/236 (0.42%)  1 0/226 (0.00%)  0
Thermal burn * 1  1/240 (0.42%)  1 0/236 (0.00%)  0 1/226 (0.44%)  1
Wound * 1  0/240 (0.00%)  0 0/236 (0.00%)  0