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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00473382
First received: May 13, 2007
Last updated: August 25, 2014
Last verified: August 2014
Results First Received: November 30, 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, Argentina, Peru, Columbia, Chile, and Peru. There were 47 patients from the Latin American countries.

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
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.
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.

Participant Flow for 3 periods

Period 1:   Core Study
    Sham Injection/Ranibizumab 0.5 mg     Ranibizumab 0.3 mg     Ranibizumab 0.5 mg  
STARTED     130     125     127  
COMPLETED     102     98     98  
NOT COMPLETED     28     27     29  
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 2:   Open-label Extension Through Month 48
    Sham Injection/Ranibizumab 0.5 mg     Ranibizumab 0.3 mg     Ranibizumab 0.5 mg  
STARTED     88 [1]   83 [1]   84 [1]
COMPLETED     38     42     37  
NOT COMPLETED     50     41     47  
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 3:   Open-label Extension Through Month 60
    Sham Injection/Ranibizumab 0.5 mg     Ranibizumab 0.3 mg     Ranibizumab 0.5 mg  
STARTED     88 [1]   83 [1]   84 [1]
COMPLETED     2     1     2  
NOT COMPLETED     86     82     82  
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.



  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     127     130     382  
Age  
[units: years]
Mean ± Standard Deviation
  62.7  ± 11.1     61.8  ± 10.1     63.5  ± 10.8     62.7  ± 10.7  
Gender  
[units: participants]
       
Female     52     47     64     163  
Male     73     80     66     219  



  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
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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.


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).

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  
Total, serious adverse events                
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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 [4]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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 [3]              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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              
# participants affected / at risk     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%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (15.1)
[3] (S)=study eye
[4] (F)=fellow eye




  Other Adverse Events


  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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