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Comparative Efficacy, Safety, and Tolerability of Rivastigmine 10 and 15 cm^2 Patch in Patients With Alzheimer's Disease (AD) Showing Cognitive Decline

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ClinicalTrials.gov Identifier: NCT00506415
Recruitment Status : Completed
First Posted : July 25, 2007
Results First Posted : September 19, 2012
Last Update Posted : September 19, 2012
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Alzheimer Disease
Interventions Drug: Rivastigmine 5 cm^2
Drug: Rivastigmine 10 cm^2
Drug: Rivastigmine 15 cm^2
Drug: Placebo to 15 cm^2 patch
Drug: Placebo to 10 cm^2 patch
Enrollment 1584

Recruitment Details  
Pre-assignment Details 1,584 participants were enrolled, 1582 received study drug during the initial open label period; of these, 567 were qualified to enter a double blind randomized period.
Arm/Group Title Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label (10 cm^2)
Hide Arm/Group Description Rivastigmine 5 cm^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm^2 transdermal patch once a day from week 4 to week 24, 36 or 48. Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period. Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period. Rivastigmine 10 cm^2 transdermal patch once a day during 48 weeks (from week 48 to week 96) open label treatment.
Period Title: Initial Open Label (Maximum 48 Weeks)
Started 1584 [1] 0 0 0
Exposed to Study Drug 1582 0 0 0
Completed 1085 0 0 0
Not Completed 499 0 0 0
Reason Not Completed
Adverse Event             272             0             0             0
Abnormal laboratory value             1             0             0             0
Abnormal test procedure results             1             0             0             0
Unsatisfactory therapeutic effect             58             0             0             0
Withdrawal by Subject             88             0             0             0
Lost to Follow-up             22             0             0             0
Administrative problem             7             0             0             0
Death             22             0             0             0
Protocol Violation             28             0             0             0
[1]
Enrolled patients.
Period Title: Double Blind (Maximum 48 Weeks )
Started 0 286 [1] 280 0
Completed 0 203 207 0
Not Completed 0 83 73 0
Reason Not Completed
Adverse Event             0             33             28             0
Death             0             5             3             0
Unsatisfactory therapeutic effect             0             13             13             0
Protocol Violation             0             5             3             0
Lost to Follow-up             0             4             6             0
Withdrawal by Subject             0             20             17             0
Administrative problems             0             3             2             0
Condition no longer requires study drug             0             0             1             0
[1]
1 patient was randomized in error and did not receive study drug, hence excluded from this arm.
Period Title: Extended Open Label (Maximum 48 Weeks)
Started 0 0 0 457 [1]
Completed 0 0 0 395
Not Completed 0 0 0 62
Reason Not Completed
Administrative problems             0             0             0             4
Adverse Event             0             0             0             18
Lost to Follow-up             0             0             0             8
Withdrawal by Subject             0             0             0             14
Protocol Violation             0             0             0             5
Unsatisfactory therapeutic effect             0             0             0             6
Death             0             0             0             7
[1]
Two participants did not receive study drug, hence excluded from this arm.
Arm/Group Title Total Patients
Hide Arm/Group Description Total number of patients enrolled in the initial open label period that may have been randomized in the double blind period or may have continued in the extended open label period.
Overall Number of Baseline Participants 1584
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1584 participants
74.93  (7.131)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1584 participants
Female
992
  62.6%
Male
592
  37.4%
1.Primary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period
Hide Description The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) subscale comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
Arm/Group Title Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Overall Number of Participants Analyzed 268 264
Mean (Standard Deviation)
Unit of Measure: units on a scale
4.9  (7.49) 4.1  (8.00)
2.Primary Outcome
Title Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period
Hide Description The Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) is a 16 item subscale of the caregiver-based ADCS-IADL scale, developed for the use in dementia studies. The ADCS-IADL total score ranges from 0 to 56, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
Arm/Group Title Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Overall Number of Participants Analyzed 271 265
Mean (Standard Deviation)
Unit of Measure: units on a scale
-6.2  (8.78) -4.4  (8.21)
3.Secondary Outcome
Title Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period
Hide Description Functional decline was defined by either an at least 1 point decrease in the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) subscale score in a visit and confirmed by the following visit/assessment or at least 2 points decrease from the double blind randomization baseline.
Time Frame 390 days was the maximum
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
Arm/Group Title Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Overall Number of Participants Analyzed 271 265
Median (95% Confidence Interval)
Unit of Measure: Time in days
90
(85 to 113)
91
(85 to 113)
4.Secondary Outcome
Title Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period
Hide Description Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part A. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. The score represents the amount of time required to complete the task. Total values for TMT part A range between 0 and 300 seconds. A negative change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog and ADCS-IADL).
Arm/Group Title Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Overall Number of Participants Analyzed 258 254
Mean (Standard Deviation)
Unit of Measure: Time in seconds
18.2  (62.57) 16.3  (66.09)
5.Secondary Outcome
Title Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period
Hide Description Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part B. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. TMT has two parts: Part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-Part B except the person must alternate between numbers and letters. Total values for TMT part B range between 0 and 420 seconds. A negative change from baseline indicates an improvement in condition.
Time Frame Baseline and week 48 of double blind period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).
Arm/Group Title Double Blind: Rivastigmine (15 cm^2) Double Blind: Rivastigmine (10 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Overall Number of Participants Analyzed 235 236
Mean (Standard Deviation)
Unit of Measure: Time in seconds
9.3  (68.80) 5.8  (65.38)
6.Secondary Outcome
Title Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period
Hide Description Change from baseline to week 48 as assessed by the Neuropsychiatric Inventory (NPI)-10 total score. The scale consists of 10 domains that are rated for both frequency (range 1-4) and severity (range 1-3). A composite score for each domain is calculated (frequency x severity) which ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then the frequency, severity and distress scores are not completed. In this case the score is 0 for the item. The sum of the composite scores yields the NPI-10 total score (range 0-120). A negative change in score indicates an improvement from baseline (symptom reduction).
Time Frame Baseline and week 48 of double blind period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population double blind (ITT-DB): included all randomized patients with an assessment at baseline and week 48, who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).
Arm/Group Title Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2)
Hide Arm/Group Description:
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Overall Number of Participants Analyzed 271 265
Mean (Standard Deviation)
Unit of Measure: units on a scale
0.9  (10.98) 1.4  (11.51)
7.Secondary Outcome
Title Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events
Hide Description [Not Specified]
Time Frame 30 days after a maximum of 96 weeks treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
Arm/Group Title Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label (10 cm^2)
Hide Arm/Group Description:
Rivastigmine 5 cm^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm^2 transdermal patch once a day from week 4 to week 24, 36 or 48.
Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Rivastigmine transdermal patch 15c m^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Rivastigmine 10 cm^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.
Overall Number of Participants Analyzed 1582 283 280 457
Measure Type: Number
Unit of Measure: Participants
1135 193 210 263
Time Frame 30 days after a maximum of 96 weeks treatment
Adverse Event Reporting Description The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
 
Arm/Group Title Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label: Rivastigmine (10 cm^2)
Hide Arm/Group Description Safety population Initial Open Label (Safety-IOL) - This population consisted of all patients who received at least 1 dose of study drug during the initial open label phase and had at least 1 post baseline safety assessment during the same phase. Safety population Double Blind (Safety-DB) - This population included all patients who were randomized, received at least 1 dose of study drug during the double blind phase and had at least 1 post-randomization safety assessment during the double blind phase. Patients were analyzed according to treatment received. Safety population Double Blind (Safety-DB) - This population included all patients who were randomized, received at least 1 dose of study drug during the double blind phase and had at least 1 post-randomization safety assessment during the double blind phase. Patients were analyzed according to treatment received. Safety population Extended Open Label (Safety-EOL) - This population consisted of all patients who received at least 1 dose of study drug during the extended open label phase and had at least 1 post baseline safety assessment during the same phase.
All-Cause Mortality
Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label: Rivastigmine (10 cm^2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label: Rivastigmine (10 cm^2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   227/1582 (14.35%)   44/283 (15.55%)   44/280 (15.71%)   59/457 (12.91%) 
Blood and lymphatic system disorders         
Anaemia  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Coagulopathy  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Haemorrhagic anaemia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lymphadenopathy  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Cardiac disorders         
Acute coronary syndrome  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Acute myocardial infarction  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Angina pectoris  1  2/1582 (0.13%)  2/283 (0.71%)  0/280 (0.00%)  1/457 (0.22%) 
Aortic valve calcification  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Arrhythmia  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Atrial fibrillation  1  9/1582 (0.57%)  2/283 (0.71%)  0/280 (0.00%)  3/457 (0.66%) 
Atrial thrombosis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Atrioventricular block complete  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Bradyarrhythmia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Bradycardia  1  3/1582 (0.19%)  1/283 (0.35%)  2/280 (0.71%)  0/457 (0.00%) 
Bundle branch block left  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Cardiac arrest  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Cardiac failure  1  8/1582 (0.51%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Cardiac failure congestive  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  1/457 (0.22%) 
Cardio-respiratory arrest  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Cardiomyopathy  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Coronary artery disease  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Coronary artery stenosis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Left ventricular failure  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Myocardial infarction  1  6/1582 (0.38%)  2/283 (0.71%)  0/280 (0.00%)  0/457 (0.00%) 
Myocardial ischaemia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Sick sinus syndrome  1  1/1582 (0.06%)  2/283 (0.71%)  1/280 (0.36%)  1/457 (0.22%) 
Sinus bradycardia  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Tachyarrhythmia  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Tachycardia  1  0/1582 (0.00%)  1/283 (0.35%)  1/280 (0.36%)  0/457 (0.00%) 
Tachycardia paroxysmal  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Ear and labyrinth disorders         
Vertigo  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Endocrine disorders         
Adrenal insufficiency  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Hyperthyroidism  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Thyroid disorder  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Eye disorders         
Cataract  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Visual acuity reduced  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastrointestinal disorders         
Abdominal discomfort  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Abdominal pain  1  5/1582 (0.32%)  0/283 (0.00%)  2/280 (0.71%)  0/457 (0.00%) 
Abdominal pain upper  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Colitis  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Colonic polyp  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Diarrhoea  1  5/1582 (0.32%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Duodenal ulcer haemorrhage  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastric ulcer haemorrhage  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastritis  1  4/1582 (0.25%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Gastrointestinal disorder  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastrointestinal inflammation  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Gastrooesophageal reflux disease  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Hernial eventration  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hiatus hernia  1  2/1582 (0.13%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Inguinal hernia  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Intestinal mass  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Intestinal obstruction  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  2/457 (0.44%) 
Irritable bowel syndrome  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Nausea  1  7/1582 (0.44%)  1/283 (0.35%)  1/280 (0.36%)  1/457 (0.22%) 
Pancreatitis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Pancreatitis acute  1  2/1582 (0.13%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Rectal haemorrhage  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  1/457 (0.22%) 
Reflux oesophagitis  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Sigmoiditis  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Small intestinal obstruction  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Vomiting  1  12/1582 (0.76%)  2/283 (0.71%)  3/280 (1.07%)  1/457 (0.22%) 
General disorders         
Abasia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Asthenia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  2/457 (0.44%) 
Catheter site haemorrhage  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Complication of device removal  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Device malfunction  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Fatigue  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Gait disturbance  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
General physical health deterioration  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Malaise  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Non-cardiac chest pain  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Oedema peripheral  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Pyrexia  1  1/1582 (0.06%)  1/283 (0.35%)  1/280 (0.36%)  0/457 (0.00%) 
Hepatobiliary disorders         
Cholecystitis  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Cholecystitis acute  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Cholelithiasis  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  2/457 (0.44%) 
Cryptogenic cirrhosis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Infections and infestations         
Abdominal sepsis  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Bacteraemia  1  0/1582 (0.00%)  2/283 (0.71%)  0/280 (0.00%)  0/457 (0.00%) 
Catheter site infection  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Cellulitis  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Cholecystitis infective  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Cystitis  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Diverticulitis  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Febrile infection  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Gastritis viral  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastroenteritis  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Gastroenteritis viral  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Herpes zoster  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Infected skin ulcer  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Infection  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Lobar pneumonia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Meningitis  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Osteomyelitis  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Pneumonia  1  7/1582 (0.44%)  2/283 (0.71%)  4/280 (1.43%)  2/457 (0.44%) 
Pyelonephritis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Renal abscess  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Respiratory tract infection  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Sepsis  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Sinusitis  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Urinary tract infection  1  7/1582 (0.44%)  4/283 (1.41%)  4/280 (1.43%)  2/457 (0.44%) 
Urosepsis  1  0/1582 (0.00%)  0/283 (0.00%)  2/280 (0.71%)  0/457 (0.00%) 
Viral infection  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Injury, poisoning and procedural complications         
Accidental overdose  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Anastomotic leak  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Cerebral haemorrhage traumatic  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Chest injury  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Concussion  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Facial bones fracture  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Fall  1  12/1582 (0.76%)  1/283 (0.35%)  3/280 (1.07%)  0/457 (0.00%) 
Femoral neck fracture  1  4/1582 (0.25%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Femur fracture  1  2/1582 (0.13%)  0/283 (0.00%)  1/280 (0.36%)  2/457 (0.44%) 
Foot fracture  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Forearm fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Fractured sacrum  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Head injury  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Hip fracture  1  7/1582 (0.44%)  2/283 (0.71%)  0/280 (0.00%)  1/457 (0.22%) 
Humerus fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Injury  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Joint dislocation  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  2/457 (0.44%) 
Joint sprain  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Ligament rupture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lower limb fracture  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Mental status changes postoperative  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Multiple injuries  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Patella fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Pelvic fracture  1  1/1582 (0.06%)  3/283 (1.06%)  0/280 (0.00%)  0/457 (0.00%) 
Radius fracture  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Rib fracture  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Soft tissue injury  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Spinal compression fracture  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Spinal fracture  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Subdural haematoma  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Thoracic vertebral fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Tibia fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Traumatic brain injury  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Traumatic fracture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Traumatic haematoma  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Upper limb fracture  1  4/1582 (0.25%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Investigations         
Cardiac enzymes increased  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Heart rate increased  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
International normalised ratio increased  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Prostatic specific antigen increased  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Metabolism and nutrition disorders         
Decreased appetite  1  1/1582 (0.06%)  0/283 (0.00%)  2/280 (0.71%)  1/457 (0.22%) 
Dehydration  1  5/1582 (0.32%)  3/283 (1.06%)  3/280 (1.07%)  1/457 (0.22%) 
Diabetes mellitus  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Failure to thrive  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Hyperglycaemia  1  1/1582 (0.06%)  2/283 (0.71%)  0/280 (0.00%)  0/457 (0.00%) 
Hyperkalaemia  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Hypoglycaemia  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hypokalaemia  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Hyponatraemia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Malnutrition  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Musculoskeletal and connective tissue disorders         
Bursitis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Groin pain  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Intervertebral disc protrusion  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Muscle spasms  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Muscular weakness  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Musculoskeletal chest pain  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Neck pain  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Osteoarthritis  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Osteoporotic fracture  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Pain in extremity  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  2/457 (0.44%) 
Periarthritis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Spinal osteoarthritis  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Synovial cyst  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Acute myeloid leukaemia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Angiomyolipoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
B-cell lymphoma  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Basal cell carcinoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Benign breast neoplasm  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Bladder cancer  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Bladder neoplasm  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Breast cancer  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Breast cancer metastatic  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Bronchial carcinoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Cholesteatoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Colon cancer  1  0/1582 (0.00%)  2/283 (0.71%)  0/280 (0.00%)  2/457 (0.44%) 
Colon neoplasm  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Colorectal cancer  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Gastric cancer  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hepatic neoplasm malignant  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Leiomyosarcoma  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  1/457 (0.22%) 
Lip and/or oral cavity cancer  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Lung adenocarcinoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lung neoplasm  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lung neoplasm malignant  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lymphoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Malignant melanoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Malignant melanoma in situ  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Metastases to liver  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Metastases to lung  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Metastases to meninges  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Metastatic neoplasm  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Oesophageal carcinoma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Prostate cancer  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Skin cancer  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Squamous cell carcinoma of skin  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Thyroid cancer  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Nervous system disorders         
Balance disorder  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Brain oedema  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Cerebellar haemorrhage  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Cerebral haemorrhage  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Cerebral ischaemia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Cerebrovascular accident  1  5/1582 (0.32%)  1/283 (0.35%)  2/280 (0.71%)  0/457 (0.00%) 
Cognitive disorder  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Coma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Convulsion  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Crying  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Dementia  1  3/1582 (0.19%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Dementia Alzheimer's type  1  3/1582 (0.19%)  2/283 (0.71%)  0/280 (0.00%)  1/457 (0.22%) 
Dizziness  1  0/1582 (0.00%)  0/283 (0.00%)  2/280 (0.71%)  1/457 (0.22%) 
Dizziness postural  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Embolic cerebral infarction  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Encephalopathy  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Epilepsy  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Extrapyramidal disorder  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Lethargy  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Loss of consciousness  1  2/1582 (0.13%)  1/283 (0.35%)  2/280 (0.71%)  0/457 (0.00%) 
Mental impairment  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Multiple system atrophy  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Neuroleptic malignant syndrome  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Neurological decompensation  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Paraesthesia  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Presyncope  1  1/1582 (0.06%)  0/283 (0.00%)  2/280 (0.71%)  1/457 (0.22%) 
Psychomotor hyperactivity  1  3/1582 (0.19%)  1/283 (0.35%)  1/280 (0.36%)  2/457 (0.44%) 
Sciatica  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Senile dementia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Status epilepticus  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Syncope  1  14/1582 (0.88%)  3/283 (1.06%)  2/280 (0.71%)  3/457 (0.66%) 
Transient ischaemic attack  1  3/1582 (0.19%)  1/283 (0.35%)  0/280 (0.00%)  1/457 (0.22%) 
VIIth nerve paralysis  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Psychiatric disorders         
Abnormal behaviour  1  1/1582 (0.06%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Aggression  1  5/1582 (0.32%)  2/283 (0.71%)  2/280 (0.71%)  0/457 (0.00%) 
Agitation  1  6/1582 (0.38%)  2/283 (0.71%)  3/280 (1.07%)  0/457 (0.00%) 
Anxiety  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Confusional state  1  3/1582 (0.19%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Delirium  1  4/1582 (0.25%)  2/283 (0.71%)  0/280 (0.00%)  0/457 (0.00%) 
Delusion  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Depressed mood  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Depression  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Disorientation  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Fear  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hallucination  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hallucination, visual  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Insomnia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Mental status changes  1  4/1582 (0.25%)  1/283 (0.35%)  0/280 (0.00%)  3/457 (0.66%) 
Panic attack  1  0/1582 (0.00%)  0/283 (0.00%)  1/280 (0.36%)  0/457 (0.00%) 
Paranoia  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Psychotic disorder  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Restlessness  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Suicidal ideation  1  0/1582 (0.00%)  2/283 (0.71%)  0/280 (0.00%)  0/457 (0.00%) 
Suicide attempt  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Renal and urinary disorders         
Dysuria  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Haematuria  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Nephrolithiasis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Obstructive uropathy  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Renal failure  1  2/1582 (0.13%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Renal failure acute  1  1/1582 (0.06%)  1/283 (0.35%)  1/280 (0.36%)  2/457 (0.44%) 
Renal infarct  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Urinary incontinence  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Urinary retention  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Reproductive system and breast disorders         
Prostatitis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Acute respiratory distress syndrome  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Asthma  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Dyspnoea  1  5/1582 (0.32%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Dyspnoea exertional  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Foreign body aspiration  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Haemothorax  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Pleurisy  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Pleuritic pain  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Pneumonia aspiration  1  2/1582 (0.13%)  0/283 (0.00%)  1/280 (0.36%)  1/457 (0.22%) 
Pneumonitis  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Pulmonary embolism  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  2/457 (0.44%) 
Respiratory distress  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Respiratory failure  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Wheezing  1  0/1582 (0.00%)  0/283 (0.00%)  0/280 (0.00%)  1/457 (0.22%) 
Skin and subcutaneous tissue disorders         
Decubitus ulcer  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Hyperhidrosis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Psoriasis  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Skin ulcer  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Vascular disorders         
Aortic aneurysm rupture  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Deep vein thrombosis  1  1/1582 (0.06%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Hypertension  1  2/1582 (0.13%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hypertensive crisis  1  1/1582 (0.06%)  0/283 (0.00%)  0/280 (0.00%)  0/457 (0.00%) 
Hypotension  1  3/1582 (0.19%)  1/283 (0.35%)  2/280 (0.71%)  1/457 (0.22%) 
Peripheral arterial occlusive disease  1  0/1582 (0.00%)  1/283 (0.35%)  0/280 (0.00%)  0/457 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Double Blind: Rivastigmine (10 cm^2) Double Blind: Rivastigmine (15 cm^2) Extended Open Label: Rivastigmine (10 cm^2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   732/1582 (46.27%)   110/283 (38.87%)   151/280 (53.93%)   112/457 (24.51%) 
Gastrointestinal disorders         
Abdominal pain upper  1  17/1582 (1.07%)  3/283 (1.06%)  9/280 (3.21%)  4/457 (0.88%) 
Diarrhoea  1  73/1582 (4.61%)  13/283 (4.59%)  18/280 (6.43%)  4/457 (0.88%) 
Nausea  1  90/1582 (5.69%)  13/283 (4.59%)  33/280 (11.79%)  11/457 (2.41%) 
Vomiting  1  68/1582 (4.30%)  12/283 (4.24%)  27/280 (9.64%)  1/457 (0.22%) 
General disorders         
Application site erythema  1  184/1582 (11.63%)  16/283 (5.65%)  18/280 (6.43%)  10/457 (2.19%) 
Application site pruritus  1  139/1582 (8.79%)  11/283 (3.89%)  11/280 (3.93%)  5/457 (1.09%) 
Application site rash  1  56/1582 (3.54%)  5/283 (1.77%)  6/280 (2.14%)  2/457 (0.44%) 
Infections and infestations         
Urinary tract infection  1  45/1582 (2.84%)  8/283 (2.83%)  11/280 (3.93%)  11/457 (2.41%) 
Injury, poisoning and procedural complications         
Fall  1  53/1582 (3.35%)  16/283 (5.65%)  19/280 (6.79%)  24/457 (5.25%) 
Investigations         
Weight decreased  1  44/1582 (2.78%)  8/283 (2.83%)  19/280 (6.79%)  12/457 (2.63%) 
Metabolism and nutrition disorders         
Decreased appetite  1  36/1582 (2.28%)  7/283 (2.47%)  16/280 (5.71%)  5/457 (1.09%) 
Nervous system disorders         
Dizziness  1  37/1582 (2.34%)  2/283 (0.71%)  10/280 (3.57%)  8/457 (1.75%) 
Headache  1  62/1582 (3.92%)  11/283 (3.89%)  11/280 (3.93%)  7/457 (1.53%) 
Psychiatric disorders         
Agitation  1  42/1582 (2.65%)  14/283 (4.95%)  12/280 (4.29%)  5/457 (1.09%) 
Anxiety  1  56/1582 (3.54%)  7/283 (2.47%)  10/280 (3.57%)  10/457 (2.19%) 
Depression  1  65/1582 (4.11%)  13/283 (4.59%)  14/280 (5.00%)  15/457 (3.28%) 
Insomnia  1  40/1582 (2.53%)  7/283 (2.47%)  11/280 (3.93%)  6/457 (1.31%) 
Renal and urinary disorders         
Urinary incontinence  1  25/1582 (1.58%)  5/283 (1.77%)  9/280 (3.21%)  6/457 (1.31%) 
Vascular disorders         
Hypertension  1  53/1582 (3.35%)  8/283 (2.83%)  9/280 (3.21%)  8/457 (1.75%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis
Phone: 862 778 8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00506415     History of Changes
Other Study ID Numbers: CENA713D2340
First Submitted: July 20, 2007
First Posted: July 25, 2007
Results First Submitted: May 1, 2012
Results First Posted: September 19, 2012
Last Update Posted: September 19, 2012