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A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RIDE) (RIDE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00473382
Recruitment Status : Completed
First Posted : May 15, 2007
Results First Posted : January 17, 2013
Last Update Posted : April 17, 2017
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Diabetes Mellitus
Macular Edema
Interventions Drug: Ranibizumab
Drug: Sham injection
Enrollment 382
Recruitment Details Patients were recruited from study sites in the United States, Argentina, Peru, Columbia, Chile, and Peru. There were 47 patients from the Latin American countries.
Pre-assignment Details  
Arm/Group Title Sham Injection/Ranibizumab 0.5 mg Ranibizumab 0.3 mg Ranibizumab 0.5 mg
Hide Arm/Group Description Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Period Title: Core Study
Started 130 125 127
Completed 102 98 98
Not Completed 28 27 29
Reason Not Completed
Adverse Event             3             1             1
Death             3             5             10
Lost to Follow-up             3             3             3
Physician Decision             1             2             2
Subject non-compliance             5             2             1
Subject needed other treatment             1             3             2
Subject's decision             12             11             10
Period Title: Open-label Extension Through Month 48
Started 88 [1] 83 [1] 84 [1]
Completed 38 42 37
Not Completed 50 41 47
Reason Not Completed
Adverse Event             0             0             1
Death             1             3             3
Lost to Follow-up             1             2             1
Subject's Decision             5             1             6
Sponsor’s Decision to Terminate Study             41             34             36
Subject Required Other Intervention             2             1             0
[1]
Not all participants who completed the core study entered the optional open-label extension.
Period Title: Open-label Extension Through Month 60
Started 88 [1] 83 [1] 84 [1]
Completed 2 1 2
Not Completed 86 82 82
Reason Not Completed
Adverse Event             0             0             2
Death             1             7             4
Lost to Follow-up             1             3             1
Subject's Decision             7             1             6
Sponsor’s Decision to Terminate Study             75             70             69
Subject Required Other Intervention             2             1             0
[1]
Not all participants who completed the core study entered the optional open-label extension.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Total
Hide Arm/Group Description Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Total of all reporting groups
Overall Number of Baseline Participants 125 127 130 382
Hide Baseline Analysis Population Description
The Baseline Characteristics of the patients enrolled in the open-label extension phase (N=88, 83, 84 patients originally randomized to the ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham injection groups, respectively) were similar to the Baseline Characteristics of the patients enrolled in the core study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 125 participants 127 participants 130 participants 382 participants
62.7  (11.1) 61.8  (10.1) 63.5  (10.8) 62.7  (10.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 125 participants 127 participants 130 participants 382 participants
Female
52
  41.6%
47
  37.0%
64
  49.2%
163
  42.7%
Male
73
  58.4%
80
  63.0%
66
  50.8%
219
  57.3%
1.Primary Outcome
Title Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Overall Number of Participants Analyzed 125 127 130
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
33.6
(25.3 to 41.9)
45.7
(37.0 to 54.3)
12.3
(6.7 to 18.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 20.8
Confidence Interval (2-Sided) 95%
11.4 to 30.2
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 33.3
Confidence Interval (2-Sided) 95%
23.8 to 42.8
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
2.Secondary Outcome
Title Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Baseline to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 125 127 130 130
Mean (Standard Deviation)
Unit of Measure: Letters
Month 24 10.9  (10.4) 12.0  (14.9) 2.3  (14.2) NA [1]   (NA)
Month 36 10.6  (12.9) 11.4  (16.3) NA [1]   (NA) 4.7  (13.3)
Month 48 (n=34,39,39,0) 11.1  (12.0) 12.4  (9.7) NA [1]   (NA) 4.6  (12.8)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 8.5
Confidence Interval (2-Sided) 95%
5.4 to 11.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 9.9
Confidence Interval (2-Sided) 95%
6.4 to 13.3
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
Hide Description VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart.
Time Frame Months 24, 36, and 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 125 127 130 130
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
Month 24
54.4
(45.7 to 63.1)
62.2
(53.8 to 70.6)
34.6
(26.4 to 42.8)
NA [1] 
(NA to NA)
Month 36
55.2
(46.5 to 63.9)
59.1
(50.5 to 67.6)
NA [1] 
(NA to NA)
42.3
(33.8 to 50.8)
Month 48 (n=39,39,0,34)
64.1
(47.2 to 78.8)
56.4
(39.6 to 72.2)
NA [1] 
(NA to NA)
47.1
(29.8 to 64.9)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 21.4
Confidence Interval (2-Sided) 95%
10.8 to 31.9
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 27.1
Confidence Interval (2-Sided) 95%
16.4 to 37.9
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
4.Secondary Outcome
Title Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 125 127 130 130
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
Month 24
98.4
(96.2 to 100.0)
96.1
(92.7 to 99.4)
91.5
(86.8 to 96.3)
NA [1] 
(NA to NA)
Month 36
96.8
(93.7 to 99.9)
96.1
(92.7 to 99.4)
NA [1] 
(NA to NA)
92.3
(87.7 to 96.9)
Month 48 (n=39,39,0,34)
97.4
(86.5 to 99.9)
97.4
(86.5 to 99.9)
NA [1] 
(NA to NA)
94.1
(80.3 to 99.3)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0119
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 7.1
Confidence Interval (2-Sided) 95%
1.7 to 12.6
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1384
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 4.5
Confidence Interval (2-Sided) 95%
-1.2 to 10.1
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
5.Secondary Outcome
Title Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Subgroup of the intent-to-treat population: All randomized patients with focal edema at baseline, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Overall Number of Participants Analyzed 44 37 42 42
Mean (Standard Deviation)
Unit of Measure: Letters
Month 24 10.5  (11.9) 12.8  (11.0) 1.9  (17.0) NA [1]   (NA)
Month 36 10.8  (12.1) 10.9  (16.6) NA [1]   (NA) 6.6  (14.4)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0102
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 8.3
Confidence Interval (2-Sided) 95%
2.0 to 14.6
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 11.2
Confidence Interval (2-Sided) 95%
5.1 to 17.3
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Hide Description Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame Baseline to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive Ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 125 127 130 130
Mean (Standard Deviation)
Unit of Measure: µm
Month 24 -259.8  (169.3) -270.7  (201.6) -125.8  (198.3) NA [1]   (NA)
Month 36 -261.8  (180.8) -266.7  (207.8) NA [1]   (NA) -213.2  (193.5)
Month 48 (n=38,39,0,33) -251.4  (173.8) -291.6  (200.7) NA [1]   (NA) -258.7  (182.3)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANCOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -111.8
Confidence Interval (2-Sided) 95%
-151.6 to -72.0
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANCOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -132.2
Confidence Interval (2-Sided) 95%
-169.7 to -94.8
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
Hide Description The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative [NP]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative [P]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Overall Number of Participants Analyzed 117 119 124 124
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
Month 24
1.7
(0 to 4.1)
0
(0 to 0)
5.6
(1.6 to 9.7)
NA [1] 
(NA to NA)
Month 36
0.9
(0 to 2.5)
0.8
(0 to 2.5)
NA [1] 
(NA to NA)
3.2
(0.1 to 6.3)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0853
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value -4.3
Confidence Interval (2-Sided) 95%
-9.3 to 0.8
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0073
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value -5.8
Confidence Interval (2-Sided) 95%
-9.8 to -1.7
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
8.Secondary Outcome
Title Percentage of Patients With Resolution of Leakage at Month 24
Hide Description Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Overall Number of Participants Analyzed 123 127 129
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
17.1
(10.4 to 23.7)
30.7
(22.7 to 38.7)
2.3
(0 to 4.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 14.0
Confidence Interval (2-Sided) 95%
6.8 to 21.1
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method Cochran-Mantel-Haenszel
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Difference in percentage at Month 24
Estimated Value 28.3
Confidence Interval (2-Sided) 95%
20.2 to 36.4
Estimation Comments The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.
9.Secondary Outcome
Title Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
Hide Description The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3.
Time Frame Baseline to Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Overall Number of Participants Analyzed 125 127 130 130
Mean (Standard Deviation)
Unit of Measure: Treatments
Month 24 0.7  (1.4) 0.3  (0.7) 1.6  (1.6) NA [1]   (NA)
Month 36 0.9  (1.8) 0.4  (0.9) NA [1]   (NA) 1.7  (1.6)
[1]
NA = not applicable, see reporting groups.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.3 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-1.3 to -0.5
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ranibizumab 0.5 mg, Sham Injection
Comments The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
Method ANOVA
Comments The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.3
Confidence Interval (2-Sided) 95%
-1.6 to -1.0
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 125 127 130
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
Month 36
36.8
(28.3 to 45.3)
40.2
(31.6 to 48.7)
19.2
(12.5 to 26.0)
Month 48 (n=39,39,34)
48.7
(32.4 to 65.2)
41.0
(25.6 to 57.9)
17.6
(6.8 to 34.5)
11.Secondary Outcome
Title Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Month 36 to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 39 39 34
Mean (Standard Deviation)
Unit of Measure: Letters
-0.9  (8.3) 0.3  (10.7) -2.6  (8.8)
12.Secondary Outcome
Title Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48
Hide Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Month 36 to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 39 39 34
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
92.3
(79.1 to 98.4)
97.4
(86.5 to 99.9)
88.2
(72.5 to 96.7)
13.Secondary Outcome
Title Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48
Hide Description Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame Month 36 to Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
Arm/Group Title Ranibizumab 0.3 mg Ranibizumab 0.5 mg Sham Injection/Ranibizumab 0.5 mg
Hide Arm/Group Description:
Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Overall Number of Participants Analyzed 38 39 33
Mean (Standard Deviation)
Unit of Measure: µm
46.1  (148.1) 44.1  (86.3) 9.6  (78.9)
Time Frame Adverse events were recorded from the first day of treatment through Month 60. The sham Months 0-36 group includes patients randomized to sham. The sham Months 0-24 group includes patients who received sham during the first 24 months of the study.
Adverse Event Reporting Description

The adverse events tables have been updated to MedDRA version 15.1 to include safety data from the open-label extension phase. Late reported adverse events from the 36-month period have also been included.

Safety evaluable population: All randomized patients who received at least 1 study treatment.

 
Arm/Group Title Sham Injection - Months 0-24 Sham Injection/Ranibizumab 0.5 mg - Months 0-36 Ranibizumab 0.3 mg - Months 0-36 Ranibizumab 0.5 mg - Months 0-36 Sham Injection/Ranibizumab 0.5 mg - Months 37-60 Ranibizumab 0.3 mg - Months 37-60 Ranibizumab 0.5 mg - Months 37-60
Hide Arm/Group Description Patients received a sham intravitreal injection monthly for 24 months. Data in this column represent the safety data in the sham group during the first 24 months of the trial when patients were receiving only sham injections. Safety data shown here are also included in the Sham/Ranibizumab 0.5 mg - Months 0-36 column. Patients received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Data in this column represent the safety data in the sham group during the entire 36 months of the trial; most patients crossed over to receive ranibizumab 0.5 mg monthly in the third year. Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36). Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36). Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36).
All-Cause Mortality
Sham Injection - Months 0-24 Sham Injection/Ranibizumab 0.5 mg - Months 0-36 Ranibizumab 0.3 mg - Months 0-36 Ranibizumab 0.5 mg - Months 0-36 Sham Injection/Ranibizumab 0.5 mg - Months 37-60 Ranibizumab 0.3 mg - Months 37-60 Ranibizumab 0.5 mg - Months 37-60
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Sham Injection - Months 0-24 Sham Injection/Ranibizumab 0.5 mg - Months 0-36 Ranibizumab 0.3 mg - Months 0-36 Ranibizumab 0.5 mg - Months 0-36 Sham Injection/Ranibizumab 0.5 mg - Months 37-60 Ranibizumab 0.3 mg - Months 37-60 Ranibizumab 0.5 mg - Months 37-60
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   54/127 (42.52%)   68/127 (53.54%)   54/125 (43.20%)   67/124 (54.03%)   19/88 (21.59%)   31/83 (37.35%)   18/84 (21.43%) 
Blood and lymphatic system disorders               
Anaemia  1  1/127 (0.79%)  1/127 (0.79%)  2/125 (1.60%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Febrile neutropenia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Thrombocytopenia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cardiac disorders               
Acute myocardial infarction  1  0/127 (0.00%)  2/127 (1.57%)  4/125 (3.20%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Angina pectoris  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  2/88 (2.27%)  0/83 (0.00%)  0/84 (0.00%) 
Angina unstable  1  2/127 (1.57%)  3/127 (2.36%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Arrhythmia  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Arteriosclerosis coronary artery  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Atrial fibrillation  1  1/127 (0.79%)  2/127 (1.57%)  3/125 (2.40%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Bradycardia  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cardiac arrest  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  3/124 (2.42%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Cardiac failure acute  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cardiac failure congestive  1  6/127 (4.72%)  7/127 (5.51%)  3/125 (2.40%)  4/124 (3.23%)  5/88 (5.68%)  2/83 (2.41%)  2/84 (2.38%) 
Cardio-respiratory arrest  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cardiogenic shock  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Coronary artery disease  1  1/127 (0.79%)  3/127 (2.36%)  2/125 (1.60%)  6/124 (4.84%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Coronary artery occlusion  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Intracardiac thrombus  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Left ventricular dysfunction  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Sick sinus syndrome  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Sinus bradycardia  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Ventricular fibrillation  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Ventricular tachycardia  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cardiac failure  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Acute coronary syndrome  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Myocardial infarction  1  6/127 (4.72%)  7/127 (5.51%)  8/125 (6.40%)  3/124 (2.42%)  0/88 (0.00%)  3/83 (3.61%)  0/84 (0.00%) 
Atrioventricular block complete  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Atrioventricular block second degree  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Ear and labyrinth disorders               
Deafness  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Endocrine disorders               
Basedow's disease  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Goitre  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hypothyroidism  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Eye disorders               
Angle closure glaucoma (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Blindness unilateral (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cataract (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  3/124 (2.42%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Choroidal neovascularisation (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Corneal opacity (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Diabetic retinal oedema (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Glaucoma (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Macular ischaemia (F)  1 [2]  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Macular oedema (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Macular oedema (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Papilloedema (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Retinal detachment (F)  1 [2]  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Retinal haemorrhage (S)  1 [1]  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Visual acuity reduced (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  2/125 (1.60%)  1/124 (0.81%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Visual acuity reduced (S)  1 [1]  2/127 (1.57%)  2/127 (1.57%)  0/125 (0.00%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Vitreous haemorrhage (F)  1 [2]  2/127 (1.57%)  3/127 (2.36%)  10/125 (8.00%)  4/124 (3.23%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Vitreous haemorrhage (S)  1 [1]  3/127 (2.36%)  4/127 (3.15%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Retinal detachment (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Retinal vein occlusion (F)  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Gastrointestinal disorders               
Appendiceal mucocoele  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Colonic polyp  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Diarrhoea  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Dysphagia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Gastric haemorrhage  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Gastritis  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Gastrointestinal haemorrhage  1  2/127 (1.57%)  2/127 (1.57%)  1/125 (0.80%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Ileus  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pancreatitis  1  0/127 (0.00%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pancreatitis acute  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Peptic ulcer haemorrhage  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Abdominal pain  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Abdominal pain upper  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Abdominal hernia  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Colitis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Small intestinal obstruction  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Proctocolitis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
General disorders               
Chest pain  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Non-cardiac chest pain  1  0/127 (0.00%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Oedema peripheral  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Death  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Multi-organ failure  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  1/84 (1.19%) 
Hepatobiliary disorders               
Bile duct obstruction  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cholecystitis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cholecystitis acute  1  1/127 (0.79%)  2/127 (1.57%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cholelithiasis  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bile duct stone  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Infections and infestations               
Abscess  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Arthritis infective  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bacteraemia  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bone abscess  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cellulitis  1  3/127 (2.36%)  3/127 (2.36%)  3/125 (2.40%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Device related sepsis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Diverticulitis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Empyema  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Endophthalmitis (F)  1 [2]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Endophthalmitis (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  3/125 (2.40%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Escherichia sepsis  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Gangrene  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Gastroenteritis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Gastroenteritis viral  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Infected skin ulcer  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  3/124 (2.42%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Infection  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Kidney infection  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Localised infection  1  1/127 (0.79%)  2/127 (1.57%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Osteomyelitis  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Osteomyelitis chronic  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pneumonia  1  5/127 (3.94%)  5/127 (3.94%)  1/125 (0.80%)  8/124 (6.45%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Pneumonia mycoplasmal  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pseudomonal sepsis  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pyelonephritis acute  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Sepsis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  2/84 (2.38%) 
Sepsis syndrome  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Urinary tract infection  1  0/127 (0.00%)  0/127 (0.00%)  2/125 (1.60%)  1/124 (0.81%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Wound infection  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bronchitis  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Escherichia infection  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Pneumonia fungal  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Influenza  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Diabetic foot infection  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Endocarditis staphylococcal  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Peritonitis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Injury, poisoning and procedural complications               
Ankle fracture  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Carbon monoxide poisoning  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cataract traumatic (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Corneal abrasion (S)  1 [1]  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Craniocerebral injury  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Drug administration error  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Expired drug administered  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Fall  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Foot fracture  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Head injury  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hip fracture  1  1/127 (0.79%)  2/127 (1.57%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Medication error (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Post procedural complication (S)  1 [1]  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Postoperative ileus  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Procedural complication (S)  1 [1]  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Road traffic accident  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Subdural haematoma  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Tendon rupture  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Upper limb fracture  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Vascular pseudoaneurysm  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Pelvic fracture  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Neck injury  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Skull fractured base  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Spinal compression fracture  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Rib fracture  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Investigations               
Blood creatinine increased  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hepatic enzyme increased  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Intraocular pressure increased (S)  1 [1]  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Metabolism and nutrition disorders               
Dehydration  1  0/127 (0.00%)  0/127 (0.00%)  2/125 (1.60%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Diabetes mellitus  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Diabetic ketoacidosis  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hyperglycaemia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hyperkalaemia  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Hypoglycaemia  1  2/127 (1.57%)  2/127 (1.57%)  1/125 (0.80%)  1/124 (0.81%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Lactic acidosis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Musculoskeletal and connective tissue disorders               
Arthralgia  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bursitis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Groin pain  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Intervertebral disc protrusion  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Monarthritis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Osteoarthritis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Polymyalgia rheumatica  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Rhabdomyolysis  1  2/127 (1.57%)  2/127 (1.57%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Rotator cuff syndrome  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Spinal column stenosis  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Spondylolisthesis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Joint swelling  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Acute leukaemia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bladder neoplasm  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Bladder papilloma  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Breast cancer  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Colon cancer  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Hepatic neoplasm malignant  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Metastatic neoplasm  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Non−hodgkin’s lymphoma  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Ovarian cancer  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pancreatic carcinoma metastatic  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pituitary tumour benign  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Prostate cancer  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Renal cancer  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Squamous cell carcinoma  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Tongue neoplasm malignant stage unspecified  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Endometrial cancer stage I  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Hepatic neoplasm malignant recurrent  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Myeloid leukaemia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Pancreatic carcinoma  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Nervous system disorders               
Carotid artery occlusion  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Carotid artery stenosis  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Cerebral haemorrhage  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cerebral infarction  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cerebrovascular accident  1  2/127 (1.57%)  2/127 (1.57%)  3/125 (2.40%)  4/124 (3.23%)  0/88 (0.00%)  2/83 (2.41%)  2/84 (2.38%) 
Convulsion  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Dizziness  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Dyskinesia  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Encephalopathy  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Hemiplegia  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hydrocephalus  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Lumbar radiculopathy  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Parkinson’s disease  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Presyncope  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Syncope  1  1/127 (0.79%)  1/127 (0.79%)  2/125 (1.60%)  1/124 (0.81%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Transient ischaemic attack  1  2/127 (1.57%)  3/127 (2.36%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
VIIth nerve paralysis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Cerebral ischaemia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Hypoglycaemic coma  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Hypoglycaemic encephalopathy  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Psychiatric disorders               
Confusional state  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Major depression  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Schizophrenia  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Suicidal ideation  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Renal and urinary disorders               
Diabetic nephropathy  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Nephrolithiasis  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Renal failure  1  3/127 (2.36%)  4/127 (3.15%)  3/125 (2.40%)  4/124 (3.23%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Renal failure acute  1  2/127 (1.57%)  2/127 (1.57%)  2/125 (1.60%)  1/124 (0.81%)  1/88 (1.14%)  3/83 (3.61%)  1/84 (1.19%) 
Renal failure chronic  1  0/127 (0.00%)  2/127 (1.57%)  2/125 (1.60%)  3/124 (2.42%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Urinary tract obstruction  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Reproductive system and breast disorders               
Benign prostatic hyperplasia  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Chronic obstructive pulmonary disease  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Dyspnoea  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  2/124 (1.61%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Pulmonary hypertension  1  1/127 (0.79%)  1/127 (0.79%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Pulmonary oedema  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Respiratory distress  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Respiratory failure  1  0/127 (0.00%)  1/127 (0.79%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Respiratory tract congestion  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Acute respiratory distress syndrome  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Pleural effusion  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Skin and subcutaneous tissue disorders               
Diabetic foot  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Angioedema  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Skin ulcer  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Surgical and medical procedures               
Hospitalisation  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Nephroureterectomy  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Stent placement  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Vascular disorders               
Aortic aneurysm  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Aortic aneurysm rupture  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Aortic stenosis  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Deep vein thrombosis  1  0/127 (0.00%)  0/127 (0.00%)  2/125 (1.60%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Femoral artery occlusion  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hypertension  1  0/127 (0.00%)  0/127 (0.00%)  2/125 (1.60%)  3/124 (2.42%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Hypertensive crisis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Hypotension  1  0/127 (0.00%)  0/127 (0.00%)  1/125 (0.80%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Orthostatic hypotension  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Peripheral arterial occlusive disease  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  2/124 (1.61%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Thrombosis  1  1/127 (0.79%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Vascular insufficiency  1  0/127 (0.00%)  1/127 (0.79%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Arteriosclerosis  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Peripheral vascular disorder  1  0/127 (0.00%)  0/127 (0.00%)  0/125 (0.00%)  0/124 (0.00%)  0/88 (0.00%)  0/83 (0.00%)  1/84 (1.19%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.1)
[1]
(S)=study eye
[2]
(F)=fellow eye
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sham Injection - Months 0-24 Sham Injection/Ranibizumab 0.5 mg - Months 0-36 Ranibizumab 0.3 mg - Months 0-36 Ranibizumab 0.5 mg - Months 0-36 Sham Injection/Ranibizumab 0.5 mg - Months 37-60 Ranibizumab 0.3 mg - Months 37-60 Ranibizumab 0.5 mg - Months 37-60
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   123/127 (96.85%)   123/127 (96.85%)   120/125 (96.00%)   121/124 (97.58%)   65/88 (73.86%)   63/83 (75.90%)   62/84 (73.81%) 
Blood and lymphatic system disorders               
Anaemia  1  13/127 (10.24%)  16/127 (12.60%)  13/125 (10.40%)  22/124 (17.74%)  3/88 (3.41%)  2/83 (2.41%)  3/84 (3.57%) 
Cardiac disorders               
Atrial fibrillation  1  4/127 (3.15%)  7/127 (5.51%)  4/125 (3.20%)  4/124 (3.23%)  2/88 (2.27%)  3/83 (3.61%)  1/84 (1.19%) 
Cardiac failure congestive  1  7/127 (5.51%)  8/127 (6.30%)  7/125 (5.60%)  3/124 (2.42%)  0/88 (0.00%)  2/83 (2.41%)  2/84 (2.38%) 
Coronary artery disease  1  4/127 (3.15%)  8/127 (6.30%)  6/125 (4.80%)  4/124 (3.23%)  2/88 (2.27%)  0/83 (0.00%)  1/84 (1.19%) 
Endocrine disorders               
Hypothyroidism  1  5/127 (3.94%)  7/127 (5.51%)  2/125 (1.60%)  4/124 (3.23%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Eye disorders               
Cataract (F)  1 [1]  29/127 (22.83%)  32/127 (25.20%)  38/125 (30.40%)  41/124 (33.06%)  5/88 (5.68%)  1/83 (1.20%)  3/84 (3.57%) 
Cataract (S)  1 [2]  35/127 (27.56%)  39/127 (30.71%)  31/125 (24.80%)  35/124 (28.23%)  5/88 (5.68%)  6/83 (7.23%)  5/84 (5.95%) 
Cataract cortical (F)  1 [1]  5/127 (3.94%)  8/127 (6.30%)  10/125 (8.00%)  3/124 (2.42%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Cataract cortical (S)  1 [2]  5/127 (3.94%)  6/127 (4.72%)  8/125 (6.40%)  5/124 (4.03%)  3/88 (3.41%)  2/83 (2.41%)  1/84 (1.19%) 
Cataract nuclear (F)  1 [1]  1/127 (0.79%)  2/127 (1.57%)  10/125 (8.00%)  5/124 (4.03%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Cataract nuclear (S)  1 [2]  3/127 (2.36%)  4/127 (3.15%)  6/125 (4.80%)  8/124 (6.45%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Cataract subcapsular (F)  1 [1]  3/127 (2.36%)  3/127 (2.36%)  7/125 (5.60%)  8/124 (6.45%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Conjunctival haemorrhage (F)  1 [1]  3/127 (2.36%)  11/127 (8.66%)  8/125 (6.40%)  14/124 (11.29%)  3/88 (3.41%)  2/83 (2.41%)  5/84 (5.95%) 
Conjunctival haemorrhage (S)  1 [2]  40/127 (31.50%)  45/127 (35.43%)  54/125 (43.20%)  63/124 (50.81%)  7/88 (7.95%)  4/83 (4.82%)  6/84 (7.14%) 
Diabetic retinal oedema (F)  1 [1]  19/127 (14.96%)  20/127 (15.75%)  25/125 (20.00%)  16/124 (12.90%)  2/88 (2.27%)  0/83 (0.00%)  1/84 (1.19%) 
Diabetic retinal oedema (S)  1 [2]  8/127 (6.30%)  8/127 (6.30%)  8/125 (6.40%)  3/124 (2.42%)  1/88 (1.14%)  1/83 (1.20%)  3/84 (3.57%) 
Diabetic retinopathy (F)  1 [1]  5/127 (3.94%)  5/127 (3.94%)  8/125 (6.40%)  10/124 (8.06%)  0/88 (0.00%)  2/83 (2.41%)  0/84 (0.00%) 
Dry eye (F)  1 [1]  8/127 (6.30%)  10/127 (7.87%)  5/125 (4.00%)  8/124 (6.45%)  5/88 (5.68%)  2/83 (2.41%)  1/84 (1.19%) 
Dry eye (S)  1 [2]  6/127 (4.72%)  8/127 (6.30%)  8/125 (6.40%)  9/124 (7.26%)  4/88 (4.55%)  3/83 (3.61%)  1/84 (1.19%) 
Eye irritation (S)  1 [2]  4/127 (3.15%)  6/127 (4.72%)  8/125 (6.40%)  7/124 (5.65%)  1/88 (1.14%)  1/83 (1.20%)  2/84 (2.38%) 
Eye pain (S)  1 [2]  10/127 (7.87%)  12/127 (9.45%)  14/125 (11.20%)  18/124 (14.52%)  0/88 (0.00%)  3/83 (3.61%)  1/84 (1.19%) 
Foreign body sensation in eyes (S)  1 [2]  7/127 (5.51%)  8/127 (6.30%)  10/125 (8.00%)  4/124 (3.23%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Lacrimation increased (S)  1 [2]  4/127 (3.15%)  6/127 (4.72%)  7/125 (5.60%)  5/124 (4.03%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Macular fibrosis (F)  1 [1]  5/127 (3.94%)  6/127 (4.72%)  13/125 (10.40%)  9/124 (7.26%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Macular fibrosis (S)  1 [2]  11/127 (8.66%)  14/127 (11.02%)  7/125 (5.60%)  8/124 (6.45%)  4/88 (4.55%)  1/83 (1.20%)  3/84 (3.57%) 
Macular oedema (F)  1 [1]  28/127 (22.05%)  37/127 (29.13%)  46/125 (36.80%)  53/124 (42.74%)  10/88 (11.36%)  8/83 (9.64%)  9/84 (10.71%) 
Macular oedema (S)  1 [2]  26/127 (20.47%)  33/127 (25.98%)  32/125 (25.60%)  26/124 (20.97%)  9/88 (10.23%)  6/83 (7.23%)  9/84 (10.71%) 
Ocular hyperaemia (S)  1 [2]  10/127 (7.87%)  10/127 (7.87%)  5/125 (4.00%)  5/124 (4.03%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Posterior capsule opacification (S)  1 [2]  4/127 (3.15%)  6/127 (4.72%)  7/125 (5.60%)  5/124 (4.03%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Retinal exudates (F)  1 [1]  16/127 (12.60%)  18/127 (14.17%)  23/125 (18.40%)  21/124 (16.94%)  0/88 (0.00%)  2/83 (2.41%)  1/84 (1.19%) 
Retinal exudates (S)  1 [2]  15/127 (11.81%)  19/127 (14.96%)  22/125 (17.60%)  20/124 (16.13%)  2/88 (2.27%)  3/83 (3.61%)  4/84 (4.76%) 
Retinal haemorrhage (F)  1 [1]  20/127 (15.75%)  31/127 (24.41%)  32/125 (25.60%)  40/124 (32.26%)  6/88 (6.82%)  9/83 (10.84%)  8/84 (9.52%) 
Retinal haemorrhage (S)  1 [2]  22/127 (17.32%)  26/127 (20.47%)  22/125 (17.60%)  34/124 (27.42%)  4/88 (4.55%)  9/83 (10.84%)  7/84 (8.33%) 
Retinal neovascularisation (F)  1 [1]  10/127 (7.87%)  13/127 (10.24%)  13/125 (10.40%)  14/124 (11.29%)  3/88 (3.41%)  1/83 (1.20%)  3/84 (3.57%) 
Retinal neovascularisation (S)  1 [2]  7/127 (5.51%)  8/127 (6.30%)  1/125 (0.80%)  1/124 (0.81%)  0/88 (0.00%)  1/83 (1.20%)  1/84 (1.19%) 
Vision blurred (S)  1 [2]  5/127 (3.94%)  5/127 (3.94%)  10/125 (8.00%)  5/124 (4.03%)  1/88 (1.14%)  2/83 (2.41%)  0/84 (0.00%) 
Vitreous detachment (F)  1 [1]  19/127 (14.96%)  20/127 (15.75%)  13/125 (10.40%)  12/124 (9.68%)  1/88 (1.14%)  3/83 (3.61%)  1/84 (1.19%) 
Vitreous detachment (S)  1 [2]  19/127 (14.96%)  22/127 (17.32%)  14/125 (11.20%)  23/124 (18.55%)  2/88 (2.27%)  2/83 (2.41%)  1/84 (1.19%) 
Vitreous floaters (F)  1 [1]  7/127 (5.51%)  8/127 (6.30%)  3/125 (2.40%)  6/124 (4.84%)  2/88 (2.27%)  3/83 (3.61%)  4/84 (4.76%) 
Vitreous floaters (S)  1 [2]  4/127 (3.15%)  6/127 (4.72%)  10/125 (8.00%)  13/124 (10.48%)  4/88 (4.55%)  1/83 (1.20%)  3/84 (3.57%) 
Vitreous haemorrhage (F)  1 [1]  12/127 (9.45%)  16/127 (12.60%)  18/125 (14.40%)  14/124 (11.29%)  5/88 (5.68%)  4/83 (4.82%)  3/84 (3.57%) 
Vitreous haemorrhage (S)  1 [2]  16/127 (12.60%)  17/127 (13.39%)  3/125 (2.40%)  4/124 (3.23%)  2/88 (2.27%)  3/83 (3.61%)  1/84 (1.19%) 
Gastrointestinal disorders               
Constipation  1  7/127 (5.51%)  9/127 (7.09%)  14/125 (11.20%)  9/124 (7.26%)  2/88 (2.27%)  2/83 (2.41%)  5/84 (5.95%) 
Diarrhoea  1  6/127 (4.72%)  6/127 (4.72%)  3/125 (2.40%)  11/124 (8.87%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Gastrooesophageal reflux disease  1  6/127 (4.72%)  6/127 (4.72%)  6/125 (4.80%)  10/124 (8.06%)  2/88 (2.27%)  1/83 (1.20%)  3/84 (3.57%) 
Nausea  1  14/127 (11.02%)  16/127 (12.60%)  14/125 (11.20%)  10/124 (8.06%)  3/88 (3.41%)  4/83 (4.82%)  2/84 (2.38%) 
Vomiting  1  9/127 (7.09%)  10/127 (7.87%)  6/125 (4.80%)  7/124 (5.65%)  0/88 (0.00%)  1/83 (1.20%)  2/84 (2.38%) 
General disorders               
Oedema peripheral  1  4/127 (3.15%)  4/127 (3.15%)  9/125 (7.20%)  8/124 (6.45%)  4/88 (4.55%)  2/83 (2.41%)  0/84 (0.00%) 
Immune system disorders               
Drug hypersensitivity  1  6/127 (4.72%)  7/127 (5.51%)  2/125 (1.60%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  2/84 (2.38%) 
Seasonal allergy  1  5/127 (3.94%)  6/127 (4.72%)  12/125 (9.60%)  9/124 (7.26%)  1/88 (1.14%)  2/83 (2.41%)  0/84 (0.00%) 
Infections and infestations               
Bronchitis  1  4/127 (3.15%)  6/127 (4.72%)  8/125 (6.40%)  12/124 (9.68%)  0/88 (0.00%)  2/83 (2.41%)  1/84 (1.19%) 
Cellulitis  1  4/127 (3.15%)  9/127 (7.09%)  5/125 (4.00%)  4/124 (3.23%)  2/88 (2.27%)  0/83 (0.00%)  0/84 (0.00%) 
Influenza  1  7/127 (5.51%)  9/127 (7.09%)  10/125 (8.00%)  13/124 (10.48%)  3/88 (3.41%)  0/83 (0.00%)  3/84 (3.57%) 
Nasopharyngitis  1  6/127 (4.72%)  10/127 (7.87%)  16/125 (12.80%)  13/124 (10.48%)  4/88 (4.55%)  3/83 (3.61%)  3/84 (3.57%) 
Pneumonia  1  4/127 (3.15%)  6/127 (4.72%)  5/125 (4.00%)  8/124 (6.45%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Sinusitis  1  12/127 (9.45%)  14/127 (11.02%)  9/125 (7.20%)  14/124 (11.29%)  4/88 (4.55%)  3/83 (3.61%)  2/84 (2.38%) 
Upper respiratory tract infection  1  12/127 (9.45%)  14/127 (11.02%)  12/125 (9.60%)  13/124 (10.48%)  3/88 (3.41%)  3/83 (3.61%)  2/84 (2.38%) 
Urinary tract infection  1  19/127 (14.96%)  24/127 (18.90%)  13/125 (10.40%)  17/124 (13.71%)  2/88 (2.27%)  5/83 (6.02%)  3/84 (3.57%) 
Injury, poisoning and procedural complications               
Corneal abrasion (S)  1 [2]  6/127 (4.72%)  8/127 (6.30%)  7/125 (5.60%)  4/124 (3.23%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Fall  1  3/127 (2.36%)  8/127 (6.30%)  10/125 (8.00%)  2/124 (1.61%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Procedural pain  1  2/127 (1.57%)  3/127 (2.36%)  1/125 (0.80%)  7/124 (5.65%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Investigations               
Blood creatinine increased  1  5/127 (3.94%)  6/127 (4.72%)  8/125 (6.40%)  5/124 (4.03%)  1/88 (1.14%)  1/83 (1.20%)  0/84 (0.00%) 
Blood glucose increased  1  8/127 (6.30%)  9/127 (7.09%)  10/125 (8.00%)  9/124 (7.26%)  1/88 (1.14%)  1/83 (1.20%)  1/84 (1.19%) 
Intraocular pressure increased (F)  1 [1]  6/127 (4.72%)  7/127 (5.51%)  7/125 (5.60%)  12/124 (9.68%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Intraocular pressure increased (S)  1 [2]  14/127 (11.02%)  17/127 (13.39%)  20/125 (16.00%)  25/124 (20.16%)  2/88 (2.27%)  2/83 (2.41%)  3/84 (3.57%) 
Blood urea increased  1  5/127 (3.94%)  6/127 (4.72%)  8/125 (6.40%)  5/124 (4.03%)  1/88 (1.14%)  0/83 (0.00%)  0/84 (0.00%) 
Metabolism and nutrition disorders               
Diabetes mellitus  1  22/127 (17.32%)  25/127 (19.69%)  19/125 (15.20%)  22/124 (17.74%)  5/88 (5.68%)  6/83 (7.23%)  5/84 (5.95%) 
Hypercholesterolaemia  1  7/127 (5.51%)  8/127 (6.30%)  13/125 (10.40%)  4/124 (3.23%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Hyperkalaemia  1  4/127 (3.15%)  4/127 (3.15%)  5/125 (4.00%)  8/124 (6.45%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Hyperlipidaemia  1  3/127 (2.36%)  4/127 (3.15%)  7/125 (5.60%)  6/124 (4.84%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Hypoglycaemia  1  6/127 (4.72%)  7/127 (5.51%)  5/125 (4.00%)  2/124 (1.61%)  3/88 (3.41%)  0/83 (0.00%)  3/84 (3.57%) 
Musculoskeletal and connective tissue disorders               
Back pain  1  11/127 (8.66%)  14/127 (11.02%)  5/125 (4.00%)  9/124 (7.26%)  0/88 (0.00%)  0/83 (0.00%)  2/84 (2.38%) 
Nervous system disorders               
Diabetic neuropathy  1  4/127 (3.15%)  6/127 (4.72%)  7/125 (5.60%)  1/124 (0.81%)  0/88 (0.00%)  0/83 (0.00%)  0/84 (0.00%) 
Dizziness  1  4/127 (3.15%)  5/127 (3.94%)  5/125 (4.00%)  7/124 (5.65%)  1/88 (1.14%)  3/83 (3.61%)  1/84 (1.19%) 
Headache  1  7/127 (5.51%)  10/127 (7.87%)  10/125 (8.00%)  7/124 (5.65%)  0/88 (0.00%)  4/83 (4.82%)  0/84 (0.00%) 
Neuropathy peripheral  1  4/127 (3.15%)  6/127 (4.72%)  9/125 (7.20%)  4/124 (3.23%)  2/88 (2.27%)  2/83 (2.41%)  1/84 (1.19%) 
Psychiatric disorders               
Anxiety  1  8/127 (6.30%)  8/127 (6.30%)  6/125 (4.80%)  3/124 (2.42%)  1/88 (1.14%)  2/83 (2.41%)  2/84 (2.38%) 
Renal and urinary disorders               
Renal failure  1  7/127 (5.51%)  7/127 (5.51%)  5/125 (4.00%)  12/124 (9.68%)  0/88 (0.00%)  1/83 (1.20%)  0/84 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Cough  1  8/127 (6.30%)  10/127 (7.87%)  17/125 (13.60%)  10/124 (8.06%)  2/88 (2.27%)  2/83 (2.41%)  4/84 (4.76%) 
Dyspnoea  1  7/127 (5.51%)  8/127 (6.30%)  3/125 (2.40%)  1/124 (0.81%)  2/88 (2.27%)  1/83 (1.20%)  1/84 (1.19%) 
Vascular disorders               
Hypertension  1  31/127 (24.41%)  35/127 (27.56%)  33/125 (26.40%)  38/124 (30.65%)  5/88 (5.68%)  3/83 (3.61%)  3/84 (3.57%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.1)
[1]
(F)=fellow eye
[2]
(S)=study eye
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.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Genentech, Inc.
Phone: 800 821-8590
EMail: genentech@druginfo.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00473382    
Other Study ID Numbers: FVF4168g
First Submitted: May 13, 2007
First Posted: May 15, 2007
Results First Submitted: November 30, 2012
Results First Posted: January 17, 2013
Last Update Posted: April 17, 2017