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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00473330
First received: May 13, 2007
Last updated: August 25, 2014
Last verified: August 2014
Results First Received: December 10, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Diabetes Mellitus
Macular Edema
Interventions: Drug: Ranibizumab
Drug: Sham injection

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients were recruited from study sites in the United States and Argentina. There were 10 patients from Argentina.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Ranibizumab 0.3 mg 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.
Ranibizumab 0.5 mg 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.
Sham Injection/Ranibizumab 0.5 mg 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.

Participant Flow for 3 periods

Period 1:   Core Study
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     125     125     127  
COMPLETED     98     100     86  
NOT COMPLETED     27     25     41  
Adverse Event                 4                 4                 1  
Death                 6                 4                 4  
Lost to Follow-up                 5                 5                 10  
Physician Decision                 2                 1                 3  
Subject Non-compliance                 1                 2                 1  
Subject Required Other Therapy                 0                 1                 3  
Subject's Decision                 9                 8                 19  

Period 2:   Open-label Extension Through Month 48
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     89 [1]   79 [1]   77 [1]
COMPLETED     63     59     50  
NOT COMPLETED     26     20     27  
Adverse Event                 0                 0                 2  
Death                 2                 0                 0  
Lost to Follow-up                 1                 0                 2  
Physician's Decision                 2                 1                 3  
Subject's Decision                 1                 3                 3  
Sponsor’s Decision to Terminate Study                 18                 15                 16  
Subject Non-compliance                 2                 1                 0  
Subject Required Other Therapy                 0                 0                 1  
[1] Not all participants who completed the core study entered the optional open-label extension.

Period 3:   Open-label Extension Through Month 60
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     89 [1]   79 [1]   77 [1]
COMPLETED     1     1     0  
NOT COMPLETED     88     78     77  
Adverse Event                 0                 0                 2  
Death                 2                 2                 1  
Lost to Follow-up                 3                 0                 4  
Physician's Decision                 2                 1                 3  
Subject's Decision                 1                 3                 4  
Sponsor’s Decision to Terminate Study                 77                 71                 62  
Subject Non-compliance                 2                 1                 0  
Subject Required Other Therapy                 1                 0                 1  
[1] Not all participants who completed the core study entered the optional open-label extension.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Ranibizumab 0.3 mg 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.
Ranibizumab 0.5 mg 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.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Total Total of all reporting groups

Baseline Measures
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Total  
Number of Participants  
[units: participants]
  125     125     127     377  
Age  
[units: years]
Mean ± Standard Deviation
  61.7  ± 8.9     62.8  ± 10.0     61.8  ± 9.8     62.1  ± 9.6  
Gender  
[units: participants]
       
Female     52     60     53     165  
Male     73     65     74     212  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24   [ Time Frame: Baseline to Month 24 ]

2.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

3.  Secondary:   Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48   [ Time Frame: Months 24, 36, and 48 ]

4.  Secondary:   Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

5.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline   [ Time Frame: Baseline to Month 36 ]

6.  Secondary:   Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

7.  Secondary:   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   [ Time Frame: Baseline to Month 36 ]

8.  Secondary:   Percentage of Patients With Resolution of Leakage at Month 24   [ Time Frame: Baseline to Month 24 ]

9.  Secondary:   Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36   [ Time Frame: Baseline to Month 36 ]

10.  Secondary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48   [ Time Frame: Baseline to Month 48 ]

11.  Secondary:   Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48   [ Time Frame: Month 36 to Month 48 ]

12.  Secondary:   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   [ Time Frame: Month 36 to Month 48 ]

13.  Secondary:   Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48   [ Time Frame: Month 36 to Month 48 ]


  Serious Adverse Events


  Other Adverse Events
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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.
Additional 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.


Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Sham Injection - Months 0-24 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.
Sham Injection/Ranibizumab 0.5 mg - Months 0-36 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.
Ranibizumab 0.3 mg - Months 0-36 Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg - Months 0-36 Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection/Ranibizumab 0.5 mg - Months 37-60 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).
Ranibizumab 0.3 mg - Months 37-60 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).
Ranibizumab 0.5 mg - Months 37-60 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).

Other 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  
Total, other (not including serious) adverse events                
# participants affected / at risk     122/124     122/124     123/125     121/125     60/76     76/90     69/79  
Blood and lymphatic system disorders                
Anaemia † 1              
# participants affected / at risk     11/124 (8.87%)     14/124 (11.29%)     20/125 (16.00%)     20/125 (16.00%)     2/76 (2.63%)     4/90 (4.44%)     3/79 (3.80%)  
Cardiac disorders                
Cardiac failure congestive † 1              
# participants affected / at risk     3/124 (2.42%)     7/124 (5.65%)     3/125 (2.40%)     13/125 (10.40%)     2/76 (2.63%)     3/90 (3.33%)     0/79 (0.00%)  
Coronary artery disease † 1              
# participants affected / at risk     2/124 (1.61%)     2/124 (1.61%)     3/125 (2.40%)     7/125 (5.60%)     1/76 (1.32%)     3/90 (3.33%)     2/79 (2.53%)  
Endocrine disorders                
Hypothyroidism † 1              
# participants affected / at risk     1/124 (0.81%)     2/124 (1.61%)     9/125 (7.20%)     6/125 (4.80%)     0/76 (0.00%)     1/90 (1.11%)     2/79 (2.53%)  
Eye disorders                
Blepharitis (F) † 1 [3]              
# participants affected / at risk     1/124 (0.81%)     2/124 (1.61%)     7/125 (5.60%)     9/125 (7.20%)     1/76 (1.32%)     1/90 (1.11%)     1/79 (1.27%)  
Blepharitis (S) † 1 [4]              
# participants affected / at risk     1/124 (0.81%)     2/124 (1.61%)     8/125 (6.40%)     7/125 (5.60%)     2/76 (2.63%)     1/90 (1.11%)     1/79 (1.27%)  
Cataract (F) † 1 [3]              
# participants affected / at risk     25/124 (20.16%)     28/124 (22.58%)     30/125 (24.00%)     23/125 (18.40%)     3/76 (3.95%)     3/90 (3.33%)     2/79 (2.53%)  
Cataract (S) † 1 [4]              
# participants affected / at risk     20/124 (16.13%)     21/124 (16.94%)     28/125 (22.40%)     21/125 (16.80%)     7/76 (9.21%)     4/90 (4.44%)     2/79 (2.53%)  
Cataract cortical (F) † 1 [3]              
# participants affected / at risk     8/124 (6.45%)     9/124 (7.26%)     7/125 (5.60%)     7/125 (5.60%)     0/76 (0.00%)     0/90 (0.00%)     1/79 (1.27%)  
Cataract cortical (S) † 1 [4]              
# participants affected / at risk     9/124 (7.26%)     10/124 (8.06%)     9/125 (7.20%)     8/125 (6.40%)     0/76 (0.00%)     0/90 (0.00%)     0/79 (0.00%)  
Cataract nuclear (F) † 1 [3]              
# participants affected / at risk     6/124 (4.84%)     8/124 (6.45%)     6/125 (4.80%)     4/125 (3.20%)     0/76 (0.00%)     3/90 (3.33%)     1/79 (1.27%)  
Cataract nuclear (S) † 1 [5]              
# participants affected / at risk     7/124 (5.65%)     8/124 (6.45%)     6/125 (4.80%)     6/125 (4.80%)     0/76 (0.00%)     3/90 (3.33%)     1/79 (1.27%)  
Cataract subcapsular (F) † 1 [3]              
# participants affected / at risk     7/124 (5.65%)     5/124 (4.03%)     5/125 (4.00%)     5/125 (4.00%)     0/76 (0.00%)     0/90 (0.00%)     0/79 (0.00%)  
Cataract subcapsular (S) † 1 [4]              
# participants affected / at risk     4/124 (3.23%)     4/124 (3.23%)     9/125 (7.20%)     9/125 (7.20%)     1/76 (1.32%)     4/90 (4.44%)     0/79 (0.00%)  
Conjunctival haemorrhage (F) † 1 [3]              
# participants affected / at risk     2/124 (1.61%)     12/124 (9.68%)     19/125 (15.20%)     19/125 (15.20%)     8/76 (10.53%)     11/90 (12.22%)     9/79 (11.39%)  
Conjunctival haemorrhage (S) † 1 [4]              
# participants affected / at risk     40/124 (32.26%)     45/124 (36.29%)     70/125 (56.00%)     66/125 (52.80%)     6/76 (7.89%)     13/90 (14.44%)     12/79 (15.19%)  
Cystoid macular oedema (F) † 1 [3]              
# participants affected / at risk     8/124 (6.45%)     10/124 (8.06%)     12/125 (9.60%)     12/125 (9.60%)     0/76 (0.00%)     2/90 (2.22%)     0/79 (0.00%)  
Cystoid macular oedema (S) † 1 [4]              
# participants affected / at risk     5/124 (4.03%)     6/124 (4.84%)     8/125 (6.40%)     4/125 (3.20%)     0/76 (0.00%)     4/90 (4.44%)     2/79 (2.53%)  
Diabetic retinal oedema (F) † 1 [3]              
# participants affected / at risk     19/124 (15.32%)     22/124 (17.74%)     23/125 (18.40%)     23/125 (18.40%)     3/76 (3.95%)     5/90 (5.56%)     5/79 (6.33%)  
Diabetic retinal oedema (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     7/124 (5.65%)     7/125 (5.60%)     10/125 (8.00%)     2/76 (2.63%)     7/90 (7.78%)     4/79 (5.06%)  
Diabetic retinopathy (F) † 1 [3]              
# participants affected / at risk     15/124 (12.10%)     16/124 (12.90%)     12/125 (9.60%)     9/125 (7.20%)     3/76 (3.95%)     3/90 (3.33%)     1/79 (1.27%)  
Diabetic retinopathy (S) † 1 [4]              
# participants affected / at risk     8/124 (6.45%)     8/124 (6.45%)     2/125 (1.60%)     4/125 (3.20%)     3/76 (3.95%)     1/90 (1.11%)     0/79 (0.00%)  
Dry eye (F) † 1 [3]              
# participants affected / at risk     6/124 (4.84%)     7/124 (5.65%)     12/125 (9.60%)     10/125 (8.00%)     1/76 (1.32%)     1/90 (1.11%)     3/79 (3.80%)  
Dry eye (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     8/124 (6.45%)     13/125 (10.40%)     11/125 (8.80%)     1/76 (1.32%)     3/90 (3.33%)     3/79 (3.80%)  
Eye irritation (S) † 1 [4]              
# participants affected / at risk     9/124 (7.26%)     9/124 (7.26%)     13/125 (10.40%)     12/125 (9.60%)     2/76 (2.63%)     3/90 (3.33%)     6/79 (7.59%)  
Eye pain (F) † 1 [3]              
# participants affected / at risk     4/124 (3.23%)     7/124 (5.65%)     10/125 (8.00%)     13/125 (10.40%)     3/76 (3.95%)     7/90 (7.78%)     5/79 (6.33%)  
Eye pain (S) † 1 [4]              
# participants affected / at risk     24/124 (19.35%)     28/124 (22.58%)     35/125 (28.00%)     30/125 (24.00%)     3/76 (3.95%)     5/90 (5.56%)     7/79 (8.86%)  
Eye pruritus (S) † 1 [4]              
# participants affected / at risk     8/124 (6.45%)     8/124 (6.45%)     7/125 (5.60%)     5/125 (4.00%)     2/76 (2.63%)     3/90 (3.33%)     2/79 (2.53%)  
Foreign body sensation in eyes (S) † 1 [4]              
# participants affected / at risk     6/124 (4.84%)     6/124 (4.84%)     17/125 (13.60%)     8/125 (6.40%)     1/76 (1.32%)     3/90 (3.33%)     1/79 (1.27%)  
Lacrimation increased (S) † 1 [4]              
# participants affected / at risk     8/124 (6.45%)     8/124 (6.45%)     8/125 (6.40%)     15/125 (12.00%)     1/76 (1.32%)     0/90 (0.00%)     1/79 (1.27%)  
Macular fibrosis (F) † 1 [3]              
# participants affected / at risk     13/124 (10.48%)     14/124 (11.29%)     15/125 (12.00%)     15/125 (12.00%)     2/76 (2.63%)     0/90 (0.00%)     2/79 (2.53%)  
Macular fibrosis (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     10/124 (8.06%)     8/125 (6.40%)     17/125 (13.60%)     2/76 (2.63%)     1/90 (1.11%)     1/79 (1.27%)  
Macular oedema (F) † 1 [3]              
# participants affected / at risk     40/124 (32.26%)     47/124 (37.90%)     45/125 (36.00%)     46/125 (36.80%)     5/76 (6.58%)     9/90 (10.00%)     11/79 (13.92%)  
Macular oedema (S) † 1 [4]              
# participants affected / at risk     24/124 (19.35%)     26/124 (20.97%)     25/125 (20.00%)     29/125 (23.20%)     3/76 (3.95%)     9/90 (10.00%)     8/79 (10.13%)  
Ocular hyperaemia (S) † 1 [4]              
# participants affected / at risk     14/124 (11.29%)     14/124 (11.29%)     20/125 (16.00%)     14/125 (11.20%)     1/76 (1.32%)     2/90 (2.22%)     2/79 (2.53%)  
Photophobia (S) † 1 [4]              
# participants affected / at risk     1/124 (0.81%)     1/124 (0.81%)     7/125 (5.60%)     5/125 (4.00%)     0/76 (0.00%)     0/90 (0.00%)     0/79 (0.00%)  
Posterior capsule opacification (F) † 1 [3]              
# participants affected / at risk     3/124 (2.42%)     4/124 (3.23%)     10/125 (8.00%)     4/125 (3.20%)     0/76 (0.00%)     1/90 (1.11%)     3/79 (3.80%)  
Retinal aneurysm (F) † 1 [3]              
# participants affected / at risk     5/124 (4.03%)     6/124 (4.84%)     10/125 (8.00%)     6/125 (4.80%)     0/76 (0.00%)     1/90 (1.11%)     1/79 (1.27%)  
Retinal aneurysm (S) † 1 [4]              
# participants affected / at risk     3/124 (2.42%)     4/124 (3.23%)     10/125 (8.00%)     6/125 (4.80%)     0/76 (0.00%)     1/90 (1.11%)     1/79 (1.27%)  
Retinal exudates (F) † 1 [6]              
# participants affected / at risk     24/124 (19.35%)     27/124 (21.77%)     22/125 (17.60%)     15/125 (12.00%)     3/76 (3.95%)     1/90 (1.11%)     0/79 (0.00%)  
Retinal exudates (S) † 1 [4]              
# participants affected / at risk     25/124 (20.16%)     28/124 (22.58%)     28/125 (22.40%)     24/125 (19.20%)     1/76 (1.32%)     4/90 (4.44%)     2/79 (2.53%)  
Retinal haemorrhage (F) † 1 [3]              
# participants affected / at risk     24/124 (19.35%)     25/124 (20.16%)     24/125 (19.20%)     37/125 (29.60%)     4/76 (5.26%)     3/90 (3.33%)     3/79 (3.80%)  
Retinal haemorrhage (S) † 1 [4]              
# participants affected / at risk     24/124 (19.35%)     26/124 (20.97%)     19/125 (15.20%)     20/125 (16.00%)     3/76 (3.95%)     3/90 (3.33%)     5/79 (6.33%)  
Retinal neovascularisation (F) † 1 [3]              
# participants affected / at risk     15/124 (12.10%)     19/124 (15.32%)     12/125 (9.60%)     18/125 (14.40%)     2/76 (2.63%)     2/90 (2.22%)     1/79 (1.27%)  
Retinal neovascularisation (S) † 1 [4]              
# participants affected / at risk     16/124 (12.90%)     18/124 (14.52%)     0/125 (0.00%)     6/125 (4.80%)     2/76 (2.63%)     3/90 (3.33%)     1/79 (1.27%)  
Vision blurred (F) † 1 [3]              
# participants affected / at risk     5/124 (4.03%)     6/124 (4.84%)     7/125 (5.60%)     6/125 (4.80%)     1/76 (1.32%)     2/90 (2.22%)     1/79 (1.27%)  
Vision blurred (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     7/124 (5.65%)     15/125 (12.00%)     11/125 (8.80%)     0/76 (0.00%)     4/90 (4.44%)     2/79 (2.53%)  
Visual acuity reduced (S) † 1 [4]              
# participants affected / at risk     8/124 (6.45%)     10/124 (8.06%)     8/125 (6.40%)     7/125 (5.60%)     1/76 (1.32%)     1/90 (1.11%)     1/79 (1.27%)  
Vitreous detachment (F) † 1 [3]              
# participants affected / at risk     16/124 (12.90%)     18/124 (14.52%)     20/125 (16.00%)     23/125 (18.40%)     2/76 (2.63%)     0/90 (0.00%)     2/79 (2.53%)  
Vitreous detachment (S) † 1 [4]              
# participants affected / at risk     18/124 (14.52%)     19/124 (15.32%)     21/125 (16.80%)     20/125 (16.00%)     1/76 (1.32%)     2/90 (2.22%)     3/79 (3.80%)  
Vitreous floaters (F) † 1 [3]              
# participants affected / at risk     5/124 (4.03%)     8/124 (6.45%)     15/125 (12.00%)     10/125 (8.00%)     4/76 (5.26%)     7/90 (7.78%)     2/79 (2.53%)  
Vitreous floaters (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     10/124 (8.06%)     22/125 (17.60%)     20/125 (16.00%)     2/76 (2.63%)     6/90 (6.67%)     4/79 (5.06%)  
Vitreous haemorrhage (F) † 1 [3]              
# participants affected / at risk     8/124 (6.45%)     11/124 (8.87%)     10/125 (8.00%)     10/125 (8.00%)     1/76 (1.32%)     5/90 (5.56%)     1/79 (1.27%)  
Vitreous haemorrhage (S) † 1 [4]              
# participants affected / at risk     16/124 (12.90%)     18/124 (14.52%)     4/125 (3.20%)     6/125 (4.80%)     1/76 (1.32%)     2/90 (2.22%)     2/79 (2.53%)  
Gastrointestinal disorders                
Constipation † 1              
# participants affected / at risk     4/124 (3.23%)     5/124 (4.03%)     13/125 (10.40%)     15/125 (12.00%)     4/76 (5.26%)     3/90 (3.33%)     1/79 (1.27%)  
Diarrhoea † 1              
# participants affected / at risk     5/124 (4.03%)     7/124 (5.65%)     12/125 (9.60%)     15/125 (12.00%)     3/76 (3.95%)     4/90 (4.44%)     4/79 (5.06%)  
Dyspepsia † 1              
# participants affected / at risk     3/124 (2.42%)     4/124 (3.23%)     7/125 (5.60%)     1/125 (0.80%)     2/76 (2.63%)     2/90 (2.22%)     1/79 (1.27%)  
Gastrooesophageal reflux disease † 1              
# participants affected / at risk     7/124 (5.65%)     11/124 (8.87%)     13/125 (10.40%)     11/125 (8.80%)     3/76 (3.95%)     5/90 (5.56%)     3/79 (3.80%)  
Nausea † 1              
# participants affected / at risk     10/124 (8.06%)     13/124 (10.48%)     16/125 (12.80%)     18/125 (14.40%)     5/76 (6.58%)     7/90 (7.78%)     5/79 (6.33%)  
Vomiting † 1              
# participants affected / at risk     7/124 (5.65%)     7/124 (5.65%)     8/125 (6.40%)     11/125 (8.80%)     3/76 (3.95%)     3/90 (3.33%)     4/79 (5.06%)  
General disorders                
Oedema peripheral † 1              
# participants affected / at risk     6/124 (4.84%)     8/124 (6.45%)     8/125 (6.40%)     13/125 (10.40%)     1/76 (1.32%)     6/90 (6.67%)     2/79 (2.53%)  
Pain † 1              
# participants affected / at risk     2/124 (1.61%)     4/124 (3.23%)     5/125 (4.00%)     8/125 (6.40%)     0/76 (0.00%)     2/90 (2.22%)     2/79 (2.53%)  
Immune system disorders                
Seasonal allergy † 1              
# participants affected / at risk     4/124 (3.23%)     6/124 (4.84%)     11/125 (8.80%)     7/125 (5.60%)     2/76 (2.63%)     3/90 (3.33%)     2/79 (2.53%)  
Infections and infestations                
Bronchitis † 1              
# participants affected / at risk     5/124 (4.03%)     9/124 (7.26%)     8/125 (6.40%)     9/125 (7.20%)     6/76 (7.89%)     3/90 (3.33%)     4/79 (5.06%)  
Influenza † 1              
# participants affected / at risk     1/124 (0.81%)     3/124 (2.42%)     10/125 (8.00%)     11/125 (8.80%)     0/76 (0.00%)     1/90 (1.11%)     5/79 (6.33%)  
Nasopharyngitis † 1              
# participants affected / at risk     9/124 (7.26%)     13/124 (10.48%)     18/125 (14.40%)     25/125 (20.00%)     6/76 (7.89%)     2/90 (2.22%)     11/79 (13.92%)  
Pneumonia † 1              
# participants affected / at risk     7/124 (5.65%)     8/124 (6.45%)     7/125 (5.60%)     5/125 (4.00%)     1/76 (1.32%)     2/90 (2.22%)     1/79 (1.27%)  
Sinusitis † 1              
# participants affected / at risk     9/124 (7.26%)     11/124 (8.87%)     6/125 (4.80%)     7/125 (5.60%)     2/76 (2.63%)     1/90 (1.11%)     3/79 (3.80%)  
Upper respiratory tract infection † 1              
# participants affected / at risk     7/124 (5.65%)     8/124 (6.45%)     11/125 (8.80%)     11/125 (8.80%)     2/76 (2.63%)     4/90 (4.44%)     4/79 (5.06%)  
Urinary tract infection † 1              
# participants affected / at risk     9/124 (7.26%)     12/124 (9.68%)     5/125 (4.00%)     14/125 (11.20%)     2/76 (2.63%)     3/90 (3.33%)     6/79 (7.59%)  
Injury, poisoning and procedural complications                
Corneal abrasion (S) † 1 [4]              
# participants affected / at risk     7/124 (5.65%)     7/124 (5.65%)     4/125 (3.20%)     4/125 (3.20%)     0/76 (0.00%)     0/90 (0.00%)     1/79 (1.27%)  
Fall † 1              
# participants affected / at risk     4/124 (3.23%)     6/124 (4.84%)     3/125 (2.40%)     7/125 (5.60%)     3/76 (3.95%)     4/90 (4.44%)     6/79 (7.59%)  
Investigations                
Blood glucose increased † 1              
# participants affected / at risk     6/124 (4.84%)     6/124 (4.84%)     8/125 (6.40%)     12/125 (9.60%)     5/76 (6.58%)     3/90 (3.33%)     2/79 (2.53%)  
Intraocular pressure increased (F) † 1 [3]              
# participants affected / at risk     4/124 (3.23%)     6/124 (4.84%)     13/125 (10.40%)     8/125 (6.40%)     0/76 (0.00%)     0/90 (0.00%)     2/79 (2.53%)  
Intraocular pressure increased (S) † 1 [4]              
# participants affected / at risk     3/124 (2.42%)     9/124 (7.26%)     26/125 (20.80%)     20/125 (16.00%)     0/76 (0.00%)     5/90 (5.56%)     2/79 (2.53%)  
Metabolism and nutrition disorders                
Diabetes mellitus † 1              
# participants affected / at risk     8/124 (6.45%)     12/124 (9.68%)     17/125 (13.60%)     13/125 (10.40%)     2/76 (2.63%)     3/90 (3.33%)     5/79 (6.33%)  
Hypercholesterolaemia † 1              
# participants affected / at risk     6/124 (4.84%)     7/124 (5.65%)     11/125 (8.80%)     9/125 (7.20%)     0/76 (0.00%)     3/90 (3.33%)     2/79 (2.53%)  
Hyperkalaemia † 1              
# participants affected / at risk     6/124 (4.84%)     8/124 (6.45%)     4/125 (3.20%)     2/125 (1.60%)     2/76 (2.63%)     1/90 (1.11%)     3/79 (3.80%)  
Hyperlipidaemia † 1              
# participants affected / at risk     6/124 (4.84%)     7/124 (5.65%)     5/125 (4.00%)     6/125 (4.80%)     0/76 (0.00%)     0/90 (0.00%)     1/79 (1.27%)  
Hypoglycaemia † 1              
# participants affected / at risk     5/124 (4.03%)     6/124 (4.84%)     8/125 (6.40%)     2/125 (1.60%)     2/76 (2.63%)     1/90 (1.11%)     2/79 (2.53%)  
Musculoskeletal and connective tissue disorders                
Arthralgia † 1              
# participants affected / at risk     4/124 (3.23%)     5/124 (4.03%)     7/125 (5.60%)     11/125 (8.80%)     5/76 (6.58%)     0/90 (0.00%)     1/79 (1.27%)  
Back pain † 1              
# participants affected / at risk     8/124 (6.45%)     13/124 (10.48%)     5/125 (4.00%)     8/125 (6.40%)     2/76 (2.63%)     4/90 (4.44%)     3/79 (3.80%)  
Pain in extremity † 1              
# participants affected / at risk     3/124 (2.42%)     4/124 (3.23%)     3/125 (2.40%)     7/125 (5.60%)     2/76 (2.63%)     1/90 (1.11%)     2/79 (2.53%)  
Nervous system disorders                
Dizziness † 1              
# participants affected / at risk     7/124 (5.65%)     10/124 (8.06%)     4/125 (3.20%)     6/125 (4.80%)     1/76 (1.32%)     2/90 (2.22%)     5/79 (6.33%)  
Headache † 1              
# participants affected / at risk     14/124 (11.29%)     20/124 (16.13%)     11/125 (8.80%)     9/125 (7.20%)     6/76 (7.89%)     2/90 (2.22%)     2/79 (2.53%)  
Neuropathy peripheral † 1              
# participants affected / at risk     3/124 (2.42%)     4/124 (3.23%)     8/125 (6.40%)     8/125 (6.40%)     0/76 (0.00%)     1/90 (1.11%)     0/79 (0.00%)  
Psychiatric disorders                
Anxiety † 1              
# participants affected / at risk     5/124 (4.03%)     6/124 (4.84%)     5/125 (4.00%)     10/125 (8.00%)     0/76 (0.00%)     2/90 (2.22%)     5/79 (6.33%)  
Depression † 1              
# participants affected / at risk     7/124 (5.65%)     9/124 (7.26%)     8/125 (6.40%)     10/125 (8.00%)     1/76 (1.32%)     1/90 (1.11%)     4/79 (5.06%)  
Insomnia † 1              
# participants affected / at risk     7/124 (5.65%)     11/124 (8.87%)     7/125 (5.60%)     5/125 (4.00%)     3/76 (3.95%)     5/90 (5.56%)     2/79 (2.53%)  
Renal and urinary disorders                
Renal failure † 1              
# participants affected / at risk     7/124 (5.65%)     9/124 (7.26%)     9/125 (7.20%)     6/125 (4.80%)     0/76 (0.00%)     0/90 (0.00%)     0/79 (0.00%)  
Renal failure chronic † 1              
# participants affected / at risk     3/124 (2.42%)     3/124 (2.42%)     7/125 (5.60%)     10/125 (8.00%)     3/76 (3.95%)     3/90 (3.33%)     2/79 (2.53%)  
Respiratory, thoracic and mediastinal disorders                
Cough † 1              
# participants affected / at risk     4/124 (3.23%)     7/124 (5.65%)     12/125 (9.60%)     8/125 (6.40%)     0/76 (0.00%)     1/90 (1.11%)     4/79 (5.06%)  
Dyspnoea † 1              
# participants affected / at risk     3/124 (2.42%)     5/124 (4.03%)     5/125 (4.00%)     8/125 (6.40%)     0/76 (0.00%)     3/90 (3.33%)     6/79 (7.59%)  
Vascular disorders                
Hypertension † 1              
# participants affected / at risk     23/124 (18.55%)     28/124 (22.58%)     27/125 (21.60%)     30/125 (24.00%)     6/76 (7.89%)     8/90 (8.89%)     8/79 (10.13%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (15.1)
[3] (F)=fellow eye
[4] (S)=study eye
[5] Study eye
[6] (F)=study eye



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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