A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD)

This study has been completed.
Sponsor:
Collaborators:
Forest Laboratories
DSM Nutritional Products, Inc.
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00235716
First received: October 6, 2005
Last updated: July 14, 2014
Last verified: July 2014
Results First Received: December 6, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Alzheimer's Disease
Interventions: Drug: dl-alpha-tocopherol
Drug: Memantine
Drug: Placebo

  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
Recruitment initiated in August, 2007 and concluded in March, 2012. Enrollment took place at 14 VA medical centers.

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
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine (Namenda) Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Participant Flow:   Overall Study
    Vitamin E     Memantine (Namenda)     Vitamin E + Memantine     Placebo  
STARTED     152     155     154     152  
COMPLETED     90     88     89     90  
NOT COMPLETED     62     67     65     62  
Death                 26                 39                 32                 31  
Withdrawal by Subject                 23                 19                 17                 18  
Lost to Follow-up                 12                 7                 14                 10  
Adverse Event                 1                 1                 1                 0  
Physician Decision                 0                 1                 1                 3  



  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.
No text entered.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine (Namenda) Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine
Total Total of all reporting groups

Baseline Measures
    Vitamin E     Memantine (Namenda)     Vitamin E + Memantine     Placebo     Total  
Number of Participants  
[units: participants]
  152     155     154     152     613  
Age  
[units: years]
Mean ± Standard Deviation
  78.6  ± 7.2     78.8  ± 7.2     78.3  ± 7.0     79.4  ± 7.0     78.8  ± 7.1  
Gender  
[units: participants]
         
Female     6     6     4     3     19  
Male     146     149     150     149     594  
Ethnicity (NIH/OMB)  
[units: participants]
         
Hispanic or Latino     17     15     15     19     66  
Not Hispanic or Latino     135     140     139     133     547  
Unknown or Not Reported     0     0     0     0     0  
Race (NIH/OMB)  
[units: participants]
         
American Indian or Alaska Native     0     0     0     1     1  
Asian     0     1     0     0     1  
Native Hawaiian or Other Pacific Islander     0     1     0     0     1  
Black or African American     21     21     18     20     80  
White     130     132     136     131     529  
More than one race     1     0     0     0     1  
Unknown or Not Reported     0     0     0     0     0  
Region of Enrollment  
[units: participants]
         
United States     152     155     154     152     613  
Education  
[units: participants]
         
<High School Graduation     41     41     26     29     137  
High School Graduation     46     48     57     56     207  
Some College     27     38     37     33     135  
College Graduation or Advanced Degree     38     28     34     34     134  
Apolipoprotein E ε4 status [1]
[units: participants]
         
Non-carriers     47     48     59     55     209  
One ε4 allele     39     44     44     38     165  
Two ε4 alleles     10     13     8     10     41  
Not Tested     56     50     43     49     198  
Concomitant Medications Acetylcholinesterase Inhibitors (AChEI)  
[units: participants]
         
Donepezil     104     100     100     96     400  
Galantamine     43     47     49     55     194  
Rivastigmine     5     8     4     1     18  
None     0     0     1     0     1  
Weeks from AChEI Initiation to Randomization  
[units: participants]
         
≤ 12 weeks     46     36     49     37     168  
> 12 weeks     105     119     104     115     443  
Missing     1     0     1     0     2  
Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory  
[units: units on a scale]
Mean ± Standard Deviation
  56.6  ± 14.9     57.3  ± 14.2     56.4  ± 14.0     56.8  ± 13.7     56.8  ± 14.2  
Mini-Mental State Examination  
[units: units on a scale]
Mean ± Standard Deviation
  21.3  ± 3.3     20.8  ± 3.8     21.3  ± 3.4     20.8  ± 3.8     21.0  ± 3.6  
Alzheimer's Disease Assessment Scale - Cognitive portion  
[units: units on a scale]
Mean ± Standard Deviation
  18.5  ± 8.8     19.5  ± 7.9     18.0  ± 8.4     19.1  ± 8.4     18.8  ± 8.4  
Neuropsychiatric Inventory  
[units: units on a scale]
Mean ± Standard Deviation
  12.2  ± 13.3     12.1  ± 13.1     12.3  ± 13.3     13.5  ± 14.2     12.5  ± 13.4  
Caregiver Activity Survey  
[units: hours per day]
Mean ± Standard Deviation
  7.3  ± 14.3     6.7  ± 9.0     6.6  ± 10.5     6.5  ± 9.2     6.8  ± 10.9  
Dependence Scale [2]
[units: participants]
         
Level 0     5     6     8     3     22  
Level 1     8     6     8     5     27  
Level 2     85     91     80     79     335  
Level 3     31     35     31     37     134  
Level 4     4     7     10     8     29  
Level 5     19     10     17     20     66  
[1] Data collected through genetic sub-study with separate informed consent.
[2] Higher the level the more dependence / less independence.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

2.  Primary:   Mini-Mental State Examination Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

3.  Primary:   Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

4.  Primary:   Neuropsychiatric Inventory Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

5.  Primary:   Caregiver Activity Survey Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

6.  Secondary:   Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)   [ Time Frame: Every 6 months to a maximum of 4 years ]

7.  Other Pre-specified:   All-cause Mortality   [ Time Frame: up to 4 years ]


  Serious Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Serious Adverse Events
    Vitamin E     Memantine     Vitamin E + Memantine     Placebo  
Total, serious adverse events          
# participants affected / at risk     82/152 (53.95%)     84/155 (54.19%)     83/154 (53.90%)     95/152 (62.50%)  
Blood and lymphatic system disorders          
Anaemia † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     1     0     1  
Microcytic anaemia † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     1     0     0  
Blood and lymphatic system disorders [3]        
# participants affected / at risk     2/152 (1.32%)     2/155 (1.29%)     0/154 (0.00%)     1/152 (0.66%)  
# events     2     2     0     1  
Cardiac disorders          
Acute coronary syndrome † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     2     0     0     0  
Acute myocardial infarction † 1        
# participants affected / at risk     1/152 (0.66%)     3/155 (1.94%)     1/154 (0.65%)     1/152 (0.66%)  
# events     1     3     1     1  
Angina pectoris † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     1     1     0  
Angina unstable † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     2/152 (1.32%)  
# events     0     0     0     2  
Arrhythmia † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     2/152 (1.32%)  
# events     1     1     0     4  
Arteriosclerosis coronary artery † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Atrial fibrillation † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     3/154 (1.95%)     3/152 (1.97%)  
# events     1     1     3     5  
Atrial flutter † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Atrioventricular block first degree † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Atrioventricular block second degree † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Bradycardia † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     2/152 (1.32%)  
# events     1     1     0     2  
Cardiac arrest † 1        
# participants affected / at risk     3/152 (1.97%)     1/155 (0.65%)     3/154 (1.95%)     1/152 (0.66%)  
# events     3     1     3     1  
Cardiac failure † 1        
# participants affected / at risk     0/152 (0.00%)     3/155 (1.94%)     1/154 (0.65%)     2/152 (1.32%)  
# events     0     3     1     2  
Cardiac failure acute † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Cardiac failure chronic † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Cardiac failure congestive † 1        
# participants affected / at risk     4/152 (2.63%)     2/155 (1.29%)     4/154 (2.60%)     5/152 (3.29%)  
# events     8     2     5     7  
Cardio-respiratory arrest † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     1     0     0  
Cardiomyopathy † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Cardiovascular disorder † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Cor pulmonale † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Coronary artery disease † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     1     0     1  
Coronary artery occlusion † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Hypertensive cardiomyopathy † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Ischaemic cardiomyopathy † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Mitral valve incompetence † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Myocardial infarction † 1        
# participants affected / at risk     6/152 (3.95%)     5/155 (3.23%)     3/154 (1.95%)     4/152 (2.63%)  
# events     7     5     3     5  
Nodal arrhythmia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Cardiac Disorders † 1 [4]        
# participants affected / at risk     19/152 (12.50%)     16/155 (10.32%)     19/154 (12.34%)     20/152 (13.16%)  
# events     30     23     21     26  
Eye disorders          
Cataract † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     1     0     0  
Gastrointestinal disorders          
Abdominal pain † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     1     0     1  
Abdominal pain upper † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     1     0     1     1  
Constipation † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     1     1     0  
Diarrhoea † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     2/154 (1.30%)     1/152 (0.66%)  
# events     0     1     2     1  
Diverticulum † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Diverticulum intestinal † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Diverticulum intestinal haemorrhagic † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     0     0     1     1  
Dysphagia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     1     1     0  
Gastrointestinal disorder † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Gastrointestinal haemorrhage † 1        
# participants affected / at risk     1/152 (0.66%)     3/155 (1.94%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     3     0     1  
Gastrointestinal obstruction † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     1     1     0  
Gastrointestinal ulcer haemorrhage † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Haematochezia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Inguinal hernia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Intestinal obstruction † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     2/154 (1.30%)     0/152 (0.00%)  
# events     0     0     2     0  
Intestinal perforation † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Large intestinal ulcer haemorrhage † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Oesophageal disorder † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Pancreatitis † 1        
# participants affected / at risk     2/152 (1.32%)     2/155 (1.29%)     0/154 (0.00%)     1/152 (0.66%)  
# events     2     2     0     1  
Pancreatitis acute † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Pancreatitis relapsing † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Peptic ulcer † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Pharyngoesophageal diverticulum † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Rectal haemorrhage † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     1     0     1  
Small intestinal haemorrhage † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Small intestinal obstruction † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Upper gastrointestinal haemorrhage † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Vomiting † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Gastrointestinal Disorders † 1 [5]        
# participants affected / at risk     13/152 (8.55%)     14/155 (9.03%)     12/154 (7.79%)     8/152 (5.26%)  
# events     13     18     13     10  
General disorders          
Adverse drug reaction † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     2/152 (1.32%)  
# events     0     0     0     2  
Asthenia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     1/152 (0.66%)  
# events     0     1     1     1  
Chest pain † 1        
# participants affected / at risk     3/152 (1.97%)     1/155 (0.65%)     3/154 (1.95%)     3/152 (1.97%)  
# events     3     1     5     4  
Complication of device insertion † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Cyst † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Death † 1        
# participants affected / at risk     2/152 (1.32%)     4/155 (2.58%)     1/154 (0.65%)     3/152 (1.97%)  
# events     2     4     1     3  
General physical health deterioration † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Hernia † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Implant site pain † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Malaise † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Medical device complication † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Multi-organ failure † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Non-cardiac chest pain † 1        
# participants affected / at risk     2/152 (1.32%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     2     0     0     0  
Oedema † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Pyrexia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     0     0     1     1  
Stent-graft endoleak † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Sudden cardiac death † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
General Disorders † 1 [6]        
# participants affected / at risk     9/152 (5.92%)     7/155 (4.52%)     8/154 (5.19%)     14/152 (9.21%)  
# events     9     8     10     15  
Hepatobiliary disorders          
Cholecystitis acute † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Cholelithiasis † 1        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     2     1     0  
Gallbladder disorder † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Hepatobiliary Disorders † 1 [7]        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     1/154 (0.65%)     2/152 (1.32%)  
# events     1     2     1     2  
Infections and infestations          
Abscess limb † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Acarodermatitis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Bacteraemia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     2/154 (1.30%)     0/152 (0.00%)  
# events     0     0     2     0  
Bronchitis † 1        
# participants affected / at risk     0/152 (0.00%)     2/155 (1.29%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     2     1     0  
Bronchopneumonia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Cellulitis † 1        
# participants affected / at risk     2/152 (1.32%)     3/155 (1.94%)     3/154 (1.95%)     0/152 (0.00%)  
# events     2     5     3     0  
Cystitis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Diverticulitis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Ear infection † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Escherichia infection † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Escherichia urinary tract infection † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Fungal infection † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Gastritis viral † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Gastroenteritis † 1        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     2     0     0  
Gastroenteritis viral † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Gastrointestinal infection † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Infected cyst † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Infection † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Latent tuberculosis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Lobar pneumonia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Mycobacterium avium complex infection † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Nasal abscess † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Osteomyelitis † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Pneumonia † 1        
# participants affected / at risk     8/152 (5.26%)     8/155 (5.16%)     15/154 (9.74%)     5/152 (3.29%)  
# events     11     9     15     5  
Sepsis † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     1     0     1  
Sporotrichosis † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Staphylococcal infection † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Tooth infection † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Upper respiratory tract infection † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Urinary tract infection † 1        
# participants affected / at risk     8/152 (5.26%)     8/155 (5.16%)     7/154 (4.55%)     4/152 (2.63%)  
# events     8     8     13     5  
Urosepsis † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Infections † 1 [8]        
# participants affected / at risk     19/152 (12.50%)     23/155 (14.84%)     31/154 (20.13%)     11/152 (7.24%)  
# events     29     31     44     13  
Injury, poisoning and procedural complications          
Accident at home † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Carbon monoxide poisoning † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Confusion postoperative † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Drug administration error † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Fall † 1        
# participants affected / at risk     15/152 (9.87%)     14/155 (9.03%)     12/154 (7.79%)     15/152 (9.87%)  
# events     17     16     14     18  
Femur fracture † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Haemodialysis-induced symptom † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Hip fracture † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Limb injury † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Post procedural complication † 1        
# participants affected / at risk     3/152 (1.97%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     3     0     0     0  
Post procedural pulmonary embolism † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Subdural haematoma † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     1     2     0  
Injury or Procedural Complications † 1 [9]        
# participants affected / at risk     18/152 (11.84%)     15/155 (9.68%)     15/154 (9.74%)     18/152 (11.84%)  
# events     22     18     17     21  
Investigations          
Blood glucose increased † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Bronchoscopy † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Coagulation factor decreased † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Cystoscopy † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Electrocardiogram change † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Heart rate increased † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Heart rate irregular † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Urine output decreased † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Weight decreased † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Investigations † 1 [10]        
# participants affected / at risk     2/152 (1.32%)     2/155 (1.29%)     4/154 (2.60%)     1/152 (0.66%)  
# events     2     2     4     1  
Metabolism and nutrition disorders          
Dehydration † 1        
# participants affected / at risk     2/152 (1.32%)     1/155 (0.65%)     0/154 (0.00%)     3/152 (1.97%)  
# events     3     1     0     3  
Diabetes mellitus inadequate control † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Diabetic ketoacidosis † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     3     0  
Failure to thrive † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     2/152 (1.32%)  
# events     1     0     0     2  
Gout † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Hyperglycaemia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Hyperglycaemic hyperosmolar nonketotic syndrome † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Hypoglycaemia † 1        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     3/154 (1.95%)     0/152 (0.00%)  
# events     1     2     3     0  
Hypophagia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Hypovolaemia † 1        
# participants affected / at risk     0/152 (0.00%)     3/155 (1.94%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     3     0     0  
Metabolism and Nutrition Disorders † 1 [11]        
# participants affected / at risk     3/152 (1.97%)     7/155 (4.52%)     7/154 (4.55%)     6/152 (3.95%)  
# events     4     7     9     6  
Musculoskeletal and connective tissue disorders          
Arthralgia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Bursitis † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Pain in extremity † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Rotator cuff syndrome † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)          
Acute myeloid leukaemia † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Bladder cancer † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Chronic lymphocytic leukaemia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Colon cancer † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Colon cancer metastatic † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Colon cancer stage III † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     0     0     0  
Gastric cancer † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Laryngeal cancer † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     2     0  
Leukaemia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Lung cancer metastatic † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Lung neoplasm malignant † 1        
# participants affected / at risk     0/152 (0.00%)     2/155 (1.29%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     2     0     1  
Mesothelioma † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Neoplasm malignant † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     1     0     0  
Non-Hodgkin's lymphoma † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Non-small cell lung cancer † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Oesophageal cancer metastatic † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Oesophageal carcinoma † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Pancreatic carcinoma † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     2     0  
Prostate cancer † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Neoplasms † 1 [12]        
# participants affected / at risk     4/152 (2.63%)     7/155 (4.52%)     4/154 (2.60%)     6/152 (3.95%)  
# events     4     8     6     6  
Nervous system disorders          
Altered state of consciousness † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Aphasia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Balance disorder † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Brain mass † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Carotid artery occlusion † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     1     0     1  
Carotid artery stenosis † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Cerebral amyloid angiopathy † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Cerebral infarction † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     2/154 (1.30%)     0/152 (0.00%)  
# events     0     0     2     0  
Cerebrovascular accident † 1        
# participants affected / at risk     2/152 (1.32%)     1/155 (0.65%)     2/154 (1.30%)     4/152 (2.63%)  
# events     2     1     2     4  
Cerebrovascular insufficiency † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Convulsion † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     1     0     1  
Dementia † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     3/152 (1.97%)  
# events     1     0     0     3  
Dementia Alzheimer's type † 1        
# participants affected / at risk     3/152 (1.97%)     3/155 (1.94%)     3/154 (1.95%)     2/152 (1.32%)  
# events     3     3     3     2  
Dizziness † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Dysarthria † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Grand mal convulsion † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Haemorrhage intracranial † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Haemorrhagic stroke † 1        
# participants affected / at risk     2/152 (1.32%)     1/155 (0.65%)     1/154 (0.65%)     0/152 (0.00%)  
# events     2     1     1     0  
Headache † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Hypoglycaemic unconsciousness † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Ischaemic stroke † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     2/152 (1.32%)  
# events     1     1     0     2  
Loss of consciousness † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     0     0     1     1  
Mental impairment † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Motor dysfunction † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Syncope † 1        
# participants affected / at risk     2/152 (1.32%)     2/155 (1.29%)     2/154 (1.30%)     4/152 (2.63%)  
# events     2     2     2     5  
Transient ischaemic attack † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     2/154 (1.30%)     1/152 (0.66%)  
# events     2     1     2     1  
Unresponsive to stimuli † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Nervous System Disorders † 1 [13]        
# participants affected / at risk     12/152 (7.89%)     15/155 (9.68%)     17/154 (11.04%)     19/152 (12.50%)  
# events     15     18     18     21  
Psychiatric disorders          
Abnormal behaviour † 1        
# participants affected / at risk     0/152 (0.00%)     2/155 (1.29%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Aggression † 1        
# participants affected / at risk     2/152 (1.32%)     2/155 (1.29%)     1/154 (0.65%)     2/152 (1.32%)  
# events     3     2     1     2  
Agitation † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     1/154 (0.65%)     2/152 (1.32%)  
# events     1     1     1     2  
Confusional state † 1        
# participants affected / at risk     4/152 (2.63%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     4     0     1     1  
Depression † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     1     0     1  
Hallucination † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Mental status changes † 1        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     2     0     1  
Parasomnia † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Psychotic behaviour † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Psychotic disorder † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Self injurious behaviour † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Suicidal ideation † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     2     0  
Psychiatric Disorders † 1 [14]        
# participants affected / at risk     8/152 (5.26%)     10/155 (6.45%)     5/154 (3.25%)     5/152 (3.29%)  
# events     10     10     7     5  
Renal and urinary disorders          
Bladder obstruction † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Haematuria † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     1     0     1  
Nephrolithiasis † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     1     0     0  
Polyuria † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     0     0     1     1  
Renal failure † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     1/154 (0.65%)     1/152 (0.66%)  
# events     1     1     1     1  
Renal failure acute † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     1/154 (0.65%)     3/152 (1.97%)  
# events     0     1     1     3  
Renal failure chronic † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Renal and Urinary Disorders † [15]        
# participants affected / at risk     2/152 (1.32%)     5/155 (3.23%)     4/154 (2.60%)     6/152 (3.95%)  
# events     2     5     4     6  
Reproductive system and breast disorders          
Epididymitis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Prostatomegaly † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Respiratory, thoracic and mediastinal disorders          
Aspiration † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Asthma † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     2  
Choking † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Chronic obstructive pulmonary disease † 1        
# participants affected / at risk     2/152 (1.32%)     3/155 (1.94%)     2/154 (1.30%)     4/152 (2.63%)  
# events     8     3     2     6  
Dyspnoea † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     1/152 (0.66%)  
# events     1     0     1     3  
Epistaxis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Pneumonia aspiration † 1        
# participants affected / at risk     0/152 (0.00%)     2/155 (1.29%)     2/154 (1.30%)     4/152 (2.63%)  
# events     0     3     2     4  
Pulmonary embolism † 1        
# participants affected / at risk     0/152 (0.00%)     2/155 (1.29%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     2     1     0  
Pulmonary haemorrhage † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Pulmonary oedema † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Pulmonary thrombosis † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Respiratory depression † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     0     0     1     0  
Respiratory failure † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     1/154 (0.65%)     1/152 (0.66%)  
# events     1     1     1     1  
Respiratory Disorders † 1 [16]        
# participants affected / at risk     5/152 (3.29%)     9/155 (5.81%)     7/154 (4.55%)     11/152 (7.24%)  
# events     12     11     8     17  
Skin and subcutaneous tissue disorders          
Decubitus ulcer † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     2     0     0  
Skin ulcer † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Skin Disorders † 1 [17]        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     3     0     0  
Social circumstances          
Respite care † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     0     0     1  
Treatment noncompliance † 1        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     2/152 (1.32%)  
# events     1     1     0     2  
Social Circumstances † 1 [18]        
# participants affected / at risk     1/152 (0.66%)     1/155 (0.65%)     0/154 (0.00%)     3/152 (1.97%)  
# events     2     1     0     3  
Surgical and medical procedures          
Arterial bypass operation † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     2     0     0     0  
Bladder neoplasm surgery † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Cardiac operation † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Cardiac pacemaker battery replacement † 1        
# participants affected / at risk     0/152 (0.00%)     1/155 (0.65%)     0/154 (0.00%)     0/152 (0.00%)  
# events     0     1     0     0  
Cardiac pacemaker insertion † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     1/154 (0.65%)     0/152 (0.00%)  
# events     1     0     1     0  
Cardiac pacemaker replacement † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Cholecystectomy † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Coronary arterial stent insertion † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     1     0     0     2  
Drug detoxification † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Hip arthroplasty † 1        
# participants affected / at risk     1/152 (0.66%)     0/155 (0.00%)     0/154 (0.00%)     0/152 (0.00%)  
# events     1     0     0     0  
Hospice care † 1        
# participants affected / at risk     0/152 (0.00%)     0/155 (0.00%)     0/154 (0.00%)     1/152 (0.66%)  
# events     0     0     0     1  
Knee arthroplasty † 1        
# participants affected / at risk     1/152 (0.66%)     2/155 (1.29%)     1/154 (0.65%)     1/152 (0.66%)