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Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD) (VIEW 2)

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ClinicalTrials.gov Identifier: NCT00637377
Recruitment Status : Completed
First Posted : March 18, 2008
Results First Posted : January 23, 2012
Last Update Posted : December 12, 2014
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Macular Degeneration
Interventions Drug: Ranibizumab
Biological: Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321)
Enrollment 1240
Recruitment Details The study was conducted at 186 study centers in 26 countries. Recruitment period: 21 Apr 2008 - 4 Sep 2009.
Pre-assignment Details 2031 participants were screened, 1240 were randomized and 1204 received at least 1 dose of study drug. 1204 participants were included in the Safety-Analysis Set (SAS). 1202 participants with at least 1 post-baseline measurement were included in the Full-Analysis Set (FAS).
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Period Title: Overall Study
Started 303 313 311 313
Participants Received Treatment 291 [1] 309 [1] 297 [1] 307 [1]
Participants Treated (FAS) 291 309 296 306
Completed 276 281 274 284
Not Completed 27 32 37 29
Reason Not Completed
Adverse Event             2             6             8             9
Death             1             3             2             1
Lack of Efficacy             0             0             1             1
Lost to Follow-up             4             1             2             2
Protocol Violation             2             1             1             0
Withdrawal by Subject             11             15             13             11
Other (no further information available)             7             6             10             5
[1]
safety population
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 Total
Hide Arm/Group Description Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks. Total of all reporting groups
Overall Number of Baseline Participants 291 309 296 306 1202
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
73.0  (9.0) 74.1  (8.5) 74.7  (8.6) 73.8  (8.6) 73.9  (8.7)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
Female
169
  58.1%
176
  57.0%
147
  49.7%
175
  57.2%
667
  55.5%
Male
122
  41.9%
133
  43.0%
149
  50.3%
131
  42.8%
535
  44.5%
[1]
Measure Description: Information retrieved from all baseline participants.
Ethnicity   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
Not Hispanic or Latino 239 259 241 251 990
Hispanic or Latino 52 50 55 55 212
[1]
Measure Description: Information retrieved from all baseline participants.
Race   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
White 213 226 219 217 875
Black or African American 1 0 1 2 4
Asian 60 67 61 69 257
Missing 17 16 15 18 66
[1]
Measure Description: Information retrieved from all baseline participants.
National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) total score   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
72.90  (19.09) 70.27  (19.41) 74.04  (18.22) 71.30  (19.06) 72.10  (18.99)
[1]
Measure Description: Information retrieved from 1201/1202 baseline participants. The possible range of the NEI VFQ-25 total score is between 0 (worst possible) and 100 (best possible).
Area of Choroidal Neovascularization (CNV)   [1] 
Mean (Standard Deviation)
Unit of measure:  Mm^2
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
7.59  (5.34) 8.25  (5.77) 7.70  (5.26) 7.75  (5.52) 7.83  (5.48)
[1]
Measure Description: Information retrieved from 1200/1202 baseline participants.
Baseline lesion type   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
Predominantly classic 70 72 80 88 310
Minimally classic 104 112 103 106 425
Occult 116 123 113 110 462
Missing 1 2 0 2 5
[1]
Measure Description: Information retrieved from 1197/1202 baseline participants.
Baseline total lesion size   [1] 
Mean (Standard Deviation)
Unit of measure:  Mm^2
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
8.01  (5.74) 8.72  (6.14) 8.17  (5.51) 8.22  (5.87) 8.28  (5.82)
[1]
Measure Description: Information retrieved from 1198/1202 baseline participants.
Best Corrected Visual Acuity (BCVA), assessed by ETDRS chart   [1] 
Mean (Standard Deviation)
Unit of measure:  Letters correctly read
Number Analyzed 291 participants 309 participants 296 participants 306 participants 1202 participants
53.8  (13.5) 52.8  (13.9) 51.6  (14.2) 51.6  (13.9) 52.4  (13.9)
[1]
Measure Description: Information retrieved from all baseline participants. Only participants with a ETDRS (Early Treatment Diabetic Retinopathy Study) Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters were included; a higher score represents better functioning.
1.Primary Outcome
Title Percentage of Participants Who Maintained Vision at Week 52 – Last Observation Carried Forward (LOCF)
Hide Description

Maintenance of vision was defined as a loss of < 15 letters in the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score (defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning.

Nominator = (Number of participants who maintained vision * 100); Denominator = Number of participants analyzed.

Time Frame At week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol Set (PPS); imputation technique: LOCF
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description:
Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Overall Number of Participants Analyzed 269 274 268 270
Measure Type: Number
Unit of Measure: Percentage of participants
94.42 95.62 96.27 95.56
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4
Comments null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 2mg Q4, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 2mg Q4).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin is set to 10. The power is 90 % according to the sample size estimation of the study protocol.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.20
Confidence Interval (2-Sided) 95%
-4.86 to 2.46
Estimation Comments The difference is calculated as Ranibizumab minus Aflibercept. A negative value favors the Aflibercept 2mg Q4 group. As adjustment of multiple comparisons a conditional sequence of statistical hypotheses is used with alpha = 0.05.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4
Comments null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 0.5mg Q4, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 0.5mg Q4).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin is set to 10. The power is 90 % according to the sample size estimation of the study protocol.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.84
Confidence Interval (2-Sided) 95%
-5.40 to 1.71
Estimation Comments The difference is calculated as Ranibizumab minus Aflibercept. A negative value favors the Aflibercept 0.5mg Q4 group. As adjustment of multiple comparisons a conditional sequence of statistical hypotheses is used with alpha = 0.05.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Comments null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 2mg Q8, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 2mg Q8).
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin is set to 10. The power is 90 % according to the sample size estimation of the study protocol.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.13
Confidence Interval (2-Sided) 95%
-4.81 to 2.55
Estimation Comments The difference is calculated as Ranibizumab minus Aflibercept. A negative value favors the Aflibercept 2mg Q8 group. As adjustment of multiple comparisons a conditional sequence of statistical hypotheses is used with alpha = 0.05.
2.Secondary Outcome
Title Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 – LOCF
Hide Description Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning.
Time Frame Baseline and at week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full-Analysis Set (FAS); imputation technique: LOCF
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description:
Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Overall Number of Participants Analyzed 291 309 296 306
Mean (Standard Deviation)
Unit of Measure: Letters correctly read
9.4  (13.5) 7.6  (12.6) 9.7  (14.1) 8.9  (14.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.076
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -1.9484
Confidence Interval (2-Sided) 95%
-4.1009 to 0.2040
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors Aflibercept 2mg Q4.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9555
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -0.0620
Confidence Interval (2-Sided) 95%
-2.2398 to 2.1158
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors Aflibercept 0.5mg Q4
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4131
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -0.9014
Confidence Interval (2-Sided) 95%
-3.0615 to 1.2587
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors the Aflibercept 2mg Q8 group
3.Secondary Outcome
Title Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 – LOCF
Hide Description

Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning.

Nominator = (Number of participants who maintained vision * 100); Denominator = Number of participants analyzed.

Time Frame At week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full-Analysis Set; imputation technique: LOCF
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description:
Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Overall Number of Participants Analyzed 291 309 296 306
Measure Type: Number
Unit of Measure: Percentage of participants
34.02 29.45 34.80 31.37
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4
Comments The null hypothesis is that the two proportions are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.229
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -4.57
Confidence Interval (2-Sided) 95%
-12.02 to 2.88
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors the Aflibercept 2mg Q4 group
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4
Comments The null hypothesis is that the two proportions are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.843
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
-6.91 to 8.46
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors the Aflibercept 0.5mg Q4 group
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Comments The null hypothesis is that the two proportions are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.490
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -2.65
Confidence Interval (2-Sided) 95%
-10.18 to 4.88
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors the Aflibercept 2mg Q8 group
4.Secondary Outcome
Title Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 – LOCF
Hide Description The possible range of the NEI VFQ-25 total score is between 0 (worst possible) and 100 (best possible).
Time Frame Baseline and at week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description:
Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Overall Number of Participants Analyzed 287 304 290 299
Mean (Standard Deviation)
Unit of Measure: Scores on a scale
6.3  (14.8) 4.5  (15.0) 5.1  (13.7) 4.9  (14.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0097
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -2.7885
Confidence Interval (2-Sided) 95%
-4.9012 to -0.6757
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors Aflibercept 2mg Q4.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3917
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -0.9320
Confidence Interval (2-Sided) 95%
-3.0658 to 1.2019
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors Aflibercept 0.5mg Q4.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0717
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -1.9470
Confidence Interval (2-Sided) 95%
-4.0659 to 0.1718
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A positive value favors Aflibercept 2mg Q8.
5.Secondary Outcome
Title Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 – LOCF
Hide Description CNV area values measured in square millimeters; lower values represent better outcomes.
Time Frame Baseline and at week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description:
Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Overall Number of Participants Analyzed 278 294 287 289
Mean (Standard Deviation)
Unit of Measure: mm^2
-4.16  (5.90) -5.95  (6.12) -4.24  (6.13) -5.16  (5.87)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0038
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -1.180
Confidence Interval (2-Sided) 95%
-1.979 to -0.382
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A negative value favors Aflibercept 2mg Q4.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6784
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value 0.170
Confidence Interval (2-Sided) 95%
-0.632 to 0.972
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A negative value favors Aflibercept 0.5mg Q4.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5mg Q4, Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Comments The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0727
Comments as adjustment of multiple comparisons a conditional sequence of statistical hypotheses (a-priori ordered hypotheses) is used with alpha = 0.05.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in Least Squares means
Estimated Value -0.733
Confidence Interval (2-Sided) 95%
-1.534 to 0.068
Estimation Comments The difference is calculated as Aflibercept minus Ranibizumab. A negative value favors Aflibercept 2mg Q8.
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Hide Arm/Group Description Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal [IVT] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks.
All-Cause Mortality
Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   65/291 (22.34%)   81/309 (26.21%)   72/297 (24.24%)   81/307 (26.38%) 
Blood and lymphatic system disorders         
Anaemia * 1  0/291 (0.00%)  2/309 (0.65%)  1/297 (0.34%)  0/307 (0.00%) 
Febrile neutropenia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Cardiac disorders         
Acute myocardial infarction * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  2/307 (0.65%) 
Angina pectoris * 1  1/291 (0.34%)  1/309 (0.32%)  1/297 (0.34%)  0/307 (0.00%) 
Angina unstable * 1  1/291 (0.34%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Aortic valve stenosis * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Arrhythmia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Arteriosclerosis coronary artery * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Atrial fibrillation * 1  2/291 (0.69%)  2/309 (0.65%)  2/297 (0.67%)  3/307 (0.98%) 
Atrial flutter * 1  0/291 (0.00%)  2/309 (0.65%)  1/297 (0.34%)  1/307 (0.33%) 
Atrioventricular block * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Bradycardia * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Cardiac arrest * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Cardiac failure * 1  1/291 (0.34%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Cardiac failure congestive * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Cardio-respiratory arrest * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Cardiogenic shock * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Coronary artery disease * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Coronary artery thrombosis * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Mitral valve incompetence * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Myocardial infarction * 1  4/291 (1.37%)  3/309 (0.97%)  3/297 (1.01%)  4/307 (1.30%) 
Myocardial ischaemia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  2/307 (0.65%) 
Palpitations * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Pericarditis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Sinus bradycardia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Supraventricular tachycardia * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Ventricular arrhythmia * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Ventricular tachycardia * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Left ventricular dysfunction * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Cardiopulmonary failure * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Acute coronary syndrome * 1  1/291 (0.34%)  2/309 (0.65%)  2/297 (0.67%)  2/307 (0.65%) 
Cardiac disorder * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Mitral valve disease * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Cardiovascular insufficiency * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  2/307 (0.65%) 
Ear and labyrinth disorders         
Vertigo * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Tympanic membrane disorder * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Eye disorders         
Blindness * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Cataract * 1  5/291 (1.72%)  4/309 (1.29%)  4/297 (1.35%)  4/307 (1.30%) 
Cataract cortical * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Cataract nuclear * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  0/307 (0.00%) 
Cataract subcapsular * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Choroidal detachment * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Hyphaema * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Iridocyclitis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Macular cyst * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Macular degeneration * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  3/307 (0.98%) 
Maculopathy * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Posterior capsule opacification * 1  2/291 (0.69%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Retinal degeneration * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Retinal detachment * 1  3/291 (1.03%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Retinal haemorrhage * 1  4/291 (1.37%)  3/309 (0.97%)  4/297 (1.35%)  2/307 (0.65%) 
Retinal pigment epitheliopathy * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Retinal vein occlusion * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Visual acuity reduced * 1  3/291 (1.03%)  5/309 (1.62%)  1/297 (0.34%)  7/307 (2.28%) 
Vitreous detachment * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Vitreous haemorrhage * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Macular hole * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Ocular retrobulbar haemorrhage * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Choroidal neovascularisation * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  2/307 (0.65%) 
Retinal pigment epithelial tear * 1  1/291 (0.34%)  0/309 (0.00%)  1/297 (0.34%)  2/307 (0.65%) 
Macular scar * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Age-related macular degeneration * 1  0/291 (0.00%)  3/309 (0.97%)  0/297 (0.00%)  1/307 (0.33%) 
Gastrointestinal disorders         
Abdominal mass * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Abdominal pain * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Abdominal pain upper * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Abnormal faeces * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Anal fistula * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Colitis * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Colonic polyp * 1  2/291 (0.69%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Constipation * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Diverticulum * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Diverticulum intestinal * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Femoral hernia * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Femoral hernia, obstructive * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Gastric ulcer * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Gastritis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Gastritis erosive * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Inguinal hernia * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  1/307 (0.33%) 
Intestinal obstruction * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Large intestine perforation * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Nausea * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Pancreatitis * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Pancreatitis acute * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Rectal polyp * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Rectal prolapse * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Small intestinal obstruction * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Lower gastrointestinal haemorrhage * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Enterovesical fistula * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Bowel movement irregularity * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
General disorders         
Asthenia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Chest pain * 1  3/291 (1.03%)  1/309 (0.32%)  1/297 (0.34%)  1/307 (0.33%) 
Chills * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Death * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Hernia * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Malaise * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Multi-organ failure * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Oedema peripheral * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Pyrexia * 1  0/291 (0.00%)  2/309 (0.65%)  0/297 (0.00%)  1/307 (0.33%) 
Disease progression * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Device malfunction * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Device dislocation * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Hepatobiliary disorders         
Bile duct stone * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Cholecystitis * 1  1/291 (0.34%)  2/309 (0.65%)  0/297 (0.00%)  0/307 (0.00%) 
Cholecystitis acute * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Cholelithiasis * 1  0/291 (0.00%)  2/309 (0.65%)  2/297 (0.67%)  0/307 (0.00%) 
Jaundice cholestatic * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Infections and infestations         
Appendicitis * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Bronchitis * 1  1/291 (0.34%)  1/309 (0.32%)  1/297 (0.34%)  1/307 (0.33%) 
Diverticulitis * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Endophthalmitis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Escherichia sepsis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Gastroenteritis * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Gastroenteritis salmonella * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Herpes zoster * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Herpes zoster ophthalmic * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Liver abscess * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Peridiverticular abscess * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Pneumonia * 1  1/291 (0.34%)  4/309 (1.29%)  2/297 (0.67%)  6/307 (1.95%) 
Pneumonia pneumococcal * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Postoperative wound infection * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Pyelonephritis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Septic shock * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Urinary tract infection * 1  2/291 (0.69%)  2/309 (0.65%)  1/297 (0.34%)  0/307 (0.00%) 
Urosepsis * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Dysentery * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Respiratory tract infection * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Gastroenteritis norovirus * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Injury, poisoning and procedural complications         
Accident * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  0/307 (0.00%) 
Ankle fracture * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Burns second degree * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Cerebral haemorrhage traumatic * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Clavicle fracture * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Concussion * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Fall * 1  2/291 (0.69%)  1/309 (0.32%)  1/297 (0.34%)  3/307 (0.98%) 
Femoral neck fracture * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Femur fracture * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Head injury * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  0/307 (0.00%) 
Hip fracture * 1  2/291 (0.69%)  1/309 (0.32%)  1/297 (0.34%)  0/307 (0.00%) 
Injury * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Jaw fracture * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Joint dislocation * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Patella fracture * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Radius fracture * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Rib fracture * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Road traffic accident * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  1/307 (0.33%) 
Skull fractured base * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Subdural haematoma * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Traumatic haematoma * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Ulna fracture * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Wrist fracture * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Lumbar vertebral fracture * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  2/307 (0.65%) 
Contusion * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Graft thrombosis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Wound haemorrhage * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Meniscus lesion * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  2/307 (0.65%) 
Post procedural complication * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Traumatic brain injury * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Joint injury * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Eye injury * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Upper limb fracture * 1  2/291 (0.69%)  1/309 (0.32%)  3/297 (1.01%)  0/307 (0.00%) 
Lower limb fracture * 1  0/291 (0.00%)  0/309 (0.00%)  2/297 (0.67%)  0/307 (0.00%) 
Spinal column injury * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Investigations         
Blood osmolarity decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Electrocardiogram QT prolonged * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Haematocrit decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Haemoglobin decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Intraocular pressure increased * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  2/307 (0.65%) 
Mean cell haemoglobin decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Mean cell volume decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Red blood cell count decreased * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Investigation * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Metabolism and nutrition disorders         
Dehydration * 1  2/291 (0.69%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Diabetes mellitus * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Gout * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Hyperglycaemia * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Hypokalaemia * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Hyponatraemia * 1  0/291 (0.00%)  0/309 (0.00%)  2/297 (0.67%)  0/307 (0.00%) 
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Arthritis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Back pain * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Dupuytren's contracture * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Lumbar spinal stenosis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Neck pain * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Osteoarthritis * 1  0/291 (0.00%)  0/309 (0.00%)  3/297 (1.01%)  1/307 (0.33%) 
Rheumatoid arthritis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Rotator cuff syndrome * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Sjogren's syndrome * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Spinal column stenosis * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Synovitis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Intervertebral disc protrusion * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Foot deformity * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Intervertebral disc degeneration * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Acute myeloid leukaemia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Basal cell carcinoma * 1  1/291 (0.34%)  0/309 (0.00%)  2/297 (0.67%)  0/307 (0.00%) 
Benign salivary gland neoplasm * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Bladder cancer * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Bladder cancer recurrent * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Bladder cancer stage 0, with cancer in situ * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Bladder neoplasm * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Breast cancer * 1  1/291 (0.34%)  0/309 (0.00%)  3/297 (1.01%)  1/307 (0.33%) 
Carcinoid tumour * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Colon cancer * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Colon cancer recurrent * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Gastric cancer * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Glioblastoma multiforme * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Lung carcinoma cell type unspecified stage IV * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Lymphoma * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Meningioma * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Metastases to bone * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Metastases to ovary * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Myelodysplastic syndrome * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Oesophageal carcinoma * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Ovarian cancer * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Pancreatic carcinoma * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Prostate cancer metastatic * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Squamous cell carcinoma * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Uterine leiomyoma * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Lung cancer metastatic * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Colon cancer metastatic * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Lung neoplasm malignant * 1  0/291 (0.00%)  0/309 (0.00%)  2/297 (0.67%)  1/307 (0.33%) 
Nervous system disorders         
Cerebral infarction * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Cerebrovascular accident * 1  2/291 (0.69%)  2/309 (0.65%)  1/297 (0.34%)  2/307 (0.65%) 
Dementia Alzheimer's type * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Epilepsy * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Headache * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Hypertensive encephalopathy * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Normal pressure hydrocephalus * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Petit mal epilepsy * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Presyncope * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Sciatica * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Subarachnoid haemorrhage * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Syncope * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Transient ischaemic attack * 1  1/291 (0.34%)  2/309 (0.65%)  0/297 (0.00%)  0/307 (0.00%) 
Brain oedema * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
VIIth nerve paralysis * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Lumbar radiculopathy * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Lacunar infarction * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Ischaemic stroke * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Nerve root compression * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Psychiatric disorders         
Confusional state * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Depression * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Renal and urinary disorders         
Nephrolithiasis * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Renal failure * 1  0/291 (0.00%)  3/309 (0.97%)  0/297 (0.00%)  2/307 (0.65%) 
Renal failure acute * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Urinary retention * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Urinary tract obstruction * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Cystitis noninfective * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Reproductive system and breast disorders         
Benign prostatic hyperplasia * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Ovarian cyst * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Uterine haemorrhage * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Vaginal prolapse * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Respiratory, thoracic and mediastinal disorders         
Acute pulmonary oedema * 1  2/291 (0.69%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Asthma * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Chronic obstructive pulmonary disease * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Cough * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Dyspnoea * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  1/307 (0.33%) 
Lung disorder * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Pleurisy * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Pneumothorax * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Pulmonary hypertension * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Sleep apnoea syndrome * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Respiratory tract congestion * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Skin and subcutaneous tissue disorders         
Dermal cyst * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Dermatitis allergic * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Erythema multiforme * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Pemphigus * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Rash * 1  0/291 (0.00%)  2/309 (0.65%)  0/297 (0.00%)  0/307 (0.00%) 
Skin necrosis * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Skin ulcer * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Urticaria * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Surgical and medical procedures         
Blepharoplasty * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Strangulated hernia repair * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Surgery * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Hip surgery * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Haematoma evacuation * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Vaginal operation * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Vascular disorders         
Circulatory collapse * 1  0/291 (0.00%)  1/309 (0.32%)  1/297 (0.34%)  1/307 (0.33%) 
Haematoma * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Hypertension * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  1/307 (0.33%) 
Hypertensive crisis * 1  1/291 (0.34%)  1/309 (0.32%)  0/297 (0.00%)  2/307 (0.65%) 
Varicose vein * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
Deep vein thrombosis * 1  0/291 (0.00%)  0/309 (0.00%)  1/297 (0.34%)  0/307 (0.00%) 
Peripheral artery aneurysm * 1  0/291 (0.00%)  0/309 (0.00%)  0/297 (0.00%)  1/307 (0.33%) 
Venous thrombosis limb * 1  0/291 (0.00%)  1/309 (0.32%)  0/297 (0.00%)  0/307 (0.00%) 
Peripheral arterial occlusive disease * 1  1/291 (0.34%)  0/309 (0.00%)  0/297 (0.00%)  0/307 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ranibizumab 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   254/291 (87.29%)   259/309 (83.82%)   251/297 (84.51%)   260/307 (84.69%) 
Cardiac disorders         
Atrioventricular block first degree * 1  16/291 (5.50%)  25/309 (8.09%)  23/297 (7.74%)  22/307 (7.17%) 
Eye disorders         
Cataract * 1  29/291 (9.97%)  36/309 (11.65%)  34/297 (11.45%)  32/307 (10.42%) 
Conjunctival haemorrhage * 1  34/291 (11.68%)  33/309 (10.68%)  46/297 (15.49%)  35/307 (11.40%) 
Conjunctivitis * 1  19/291 (6.53%)  14/309 (4.53%)  8/297 (2.69%)  21/307 (6.84%) 
Dry eye * 1  14/291 (4.81%)  12/309 (3.88%)  15/297 (5.05%)  16/307 (5.21%) 
Eye pain * 1  28/291 (9.62%)  36/309 (11.65%)  25/297 (8.42%)  24/307 (7.82%) 
Macular cyst * 1  18/291 (6.19%)  8/309 (2.59%)  9/297 (3.03%)  9/307 (2.93%) 
Macular degeneration * 1  37/291 (12.71%)  35/309 (11.33%)  42/297 (14.14%)  51/307 (16.61%) 
Macular oedema * 1  17/291 (5.84%)  16/309 (5.18%)  23/297 (7.74%)  22/307 (7.17%) 
Maculopathy * 1  13/291 (4.47%)  16/309 (5.18%)  18/297 (6.06%)  10/307 (3.26%) 
Ocular hyperaemia * 1  20/291 (6.87%)  18/309 (5.83%)  17/297 (5.72%)  10/307 (3.26%) 
Retinal cyst * 1  13/291 (4.47%)  20/309 (6.47%)  17/297 (5.72%)  13/307 (4.23%) 
Retinal degeneration * 1  33/291 (11.34%)  37/309 (11.97%)  27/297 (9.09%)  23/307 (7.49%) 
Retinal haemorrhage * 1  82/291 (28.18%)  84/309 (27.18%)  70/297 (23.57%)  82/307 (26.71%) 
Retinal oedema * 1  34/291 (11.68%)  32/309 (10.36%)  31/297 (10.44%)  40/307 (13.03%) 
Retinal pigment epitheliopathy * 1  28/291 (9.62%)  23/309 (7.44%)  20/297 (6.73%)  28/307 (9.12%) 
Visual acuity reduced * 1  46/291 (15.81%)  44/309 (14.24%)  55/297 (18.52%)  60/307 (19.54%) 
Vitreous detachment * 1  22/291 (7.56%)  30/309 (9.71%)  17/297 (5.72%)  24/307 (7.82%) 
Conjunctival hyperaemia * 1  18/291 (6.19%)  8/309 (2.59%)  11/297 (3.70%)  5/307 (1.63%) 
Detachment of retinal pigment epithelium * 1  38/291 (13.06%)  37/309 (11.97%)  33/297 (11.11%)  31/307 (10.10%) 
Choroidal neovascularisation * 1  28/291 (9.62%)  25/309 (8.09%)  28/297 (9.43%)  23/307 (7.49%) 
Age-related macular degeneration * 1  26/291 (8.93%)  28/309 (9.06%)  26/297 (8.75%)  38/307 (12.38%) 
Gastrointestinal disorders         
Diarrhoea * 1  14/291 (4.81%)  9/309 (2.91%)  16/297 (5.39%)  16/307 (5.21%) 
General disorders         
Pyrexia * 1  19/291 (6.53%)  12/309 (3.88%)  19/297 (6.40%)  8/307 (2.61%) 
Infections and infestations         
Bronchitis * 1  13/291 (4.47%)  17/309 (5.50%)  20/297 (6.73%)  12/307 (3.91%) 
Influenza * 1  14/291 (4.81%)  19/309 (6.15%)  12/297 (4.04%)  23/307 (7.49%) 
Nasopharyngitis * 1  39/291 (13.40%)  25/309 (8.09%)  32/297 (10.77%)  26/307 (8.47%) 
Investigations         
Blood glucose increased * 1  9/291 (3.09%)  17/309 (5.50%)  14/297 (4.71%)  18/307 (5.86%) 
Intraocular pressure increased * 1  37/291 (12.71%)  38/309 (12.30%)  24/297 (8.08%)  29/307 (9.45%) 
Musculoskeletal and connective tissue disorders         
Arthralgia * 1  11/291 (3.78%)  8/309 (2.59%)  15/297 (5.05%)  7/307 (2.28%) 
Back pain * 1  17/291 (5.84%)  19/309 (6.15%)  12/297 (4.04%)  16/307 (5.21%) 
Nervous system disorders         
Dizziness * 1  15/291 (5.15%)  8/309 (2.59%)  4/297 (1.35%)  5/307 (1.63%) 
Headache * 1  14/291 (4.81%)  12/309 (3.88%)  16/297 (5.39%)  20/307 (6.51%) 
Vascular disorders         
Hypertension * 1  42/291 (14.43%)  41/309 (13.27%)  33/297 (11.11%)  34/307 (11.07%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
The conditional sequence of hypothesis testing had to stop after testing the first superiority hypothesis. Therefore, all further statistical tests are exploratory tests.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Confidentiality agreement with sponsor, contract with the sponsor via the CRO (Clinical research organization), set up based on local legal requirements, changes addressed+confirmed with local responsible persons; PIs interested in presenting the study on meetings, contacted the sponsor and received slides and approval to do so either by the Clinical Lead or the Medical Affairs department
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: BAYER
EMail: clinical-trials-contact@bayerhealthcare.com
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00637377     History of Changes
Other Study ID Numbers: 91689
2007-000583-25 ( EudraCT Number )
First Submitted: March 12, 2008
First Posted: March 18, 2008
Results First Submitted: December 16, 2011
Results First Posted: January 23, 2012
Last Update Posted: December 12, 2014