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Valproate in Dementia (VALID)

This study has been completed.
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov Identifier:
NCT00071721
First received: October 29, 2003
Last updated: September 15, 2014
Last verified: September 2014
Results First Received: July 6, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Alzheimer Disease
Interventions: Drug: Valproate
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
No text entered.

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Participant Flow:   Overall Study
    Valproate   Placebo
STARTED   153   160 
COMPLETED   81   69 
NOT COMPLETED   72   91 



  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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Total Total of all reporting groups

Baseline Measures
   Valproate   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 153   160   313 
Age 
[Units: Years]
Mean (Standard Deviation)
 74.9  (8.2)   76.6  (7.4)   75.7  (7.8) 
Gender 
[Units: Participants]
     
Female   83   101   184 
Male   70   59   129 
Region of Enrollment 
[Units: Participants]
     
United States   153   160   313 
ADAScog [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 29.4  (8.9)   30.1  (9.8)   29.8  (9.4) 
[1] Alzheimer's Disease Assessment Scale, cognitive sub-scale in points per year (ADAS-cog) is a psychometric measure sensitive to change in mild to moderate AD. The range of this instrument is 0 to 70 with higher numbers indicating greater impairment.
ADCS-ADL [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 56.9  (11.8)   54.9  (13)   55.9  (12.4) 
[1] Alzheimer's Disease Cooperative Study Activities of Daily Living Score (ADCS-ADL) is a structured questionnaire about activities of daily living, administered to the subject's caregiver/study partner. The range of this instrument is 0 to 78 with lower numbers indicating greater impairment.
CDR-SOB [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 7.1  (2.7)   7.5  (3.1)   7.3  (2.9) 
[1] Clinical Dementia Rating, Sum of Boxes (CDR-SOB) is a global rating of dementia severity based on the clinician's interpretation of the history and examination. The range of this instrument is 0 to 18 with higher numbers indicating greater impairment.
CMAI [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 10.9  (8.9)   11.9  (10.4)   11.4  (9.7) 
[1] The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item caregiver rating questionnaire for the assessment of agitation in older persons. It includes descriptions of 29 agitated behaviors, each rated on a 7-point scale of frequency. The range of this instrument is 29 to 203 with higher numbers indicating greater impairment.
NPI [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 2.6  (2.6)   3.1  (2.6)   2.9  (2.6) 
[1] The Neuropsychiatric Inventory (NPI) quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment.


  Outcome Measures
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1.  Primary:   Presence of Agitation and/or Psychosis Measured by the Neuropsychiatric Inventory (NPI) Combined With an Assessment of the Clinical Significance of Behavioral Change Rated by the Study Clinician   [ Time Frame: 24 months ]

Measure Type Primary
Measure Title Presence of Agitation and/or Psychosis Measured by the Neuropsychiatric Inventory (NPI) Combined With an Assessment of the Clinical Significance of Behavioral Change Rated by the Study Clinician
Measure Description NPI quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, and others. This is a questionnaire administered to the subject's study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment. To determine whether or not psychosis or agitation is present, there is no cutoff score but is based on the clinician’s judgment. In the NPI, the subject responds to ‘Yes’ or ‘No’ questions. Then it is determined how often psychosis or agitation occurs and if it is mild, moderate or severe.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Presence of Agitation and/or Psychosis Measured by the Neuropsychiatric Inventory (NPI) Combined With an Assessment of the Clinical Significance of Behavioral Change Rated by the Study Clinician 
[Units: Participants]
 25   29 


Statistical Analysis 1 for Presence of Agitation and/or Psychosis Measured by the Neuropsychiatric Inventory (NPI) Combined With an Assessment of the Clinical Significance of Behavioral Change Rated by the Study Clinician
Groups [1] All groups
Method [2] Cox Proportional Hazards
P Value [3] 0.88
Cox Proportional Hazard [4] 0.958
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)   [ Time Frame: 24 months ]

Measure Type Secondary
Measure Title Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)
Measure Description Alzheimer's Disease Assessment Scale, cognitive sub-scale in points per year (ADAS-cog) is a psychometric measure sensitive to change in mild to moderate AD. The range of this instrument is 0 to 70 with higher numbers indicating greater impairment.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog) 
[Units: Units on a scale]
Mean (Standard Deviation)
 42.3  (14.3)   41.9  (14.4) 

No statistical analysis provided for Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)



3.  Secondary:   Functional Performance Assessed by the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory   [ Time Frame: 24 months ]

Measure Type Secondary
Measure Title Functional Performance Assessed by the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory
Measure Description Alzheimer's Disease Cooperative Study Activities of Daily Living Score (ADCS-ADL) is a structured questionnaire about activities of daily living, administered to the subject's caregiver/study partner. The range of this instrument is 0 to 78 with lower numbers indicating greater impairment.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Functional Performance Assessed by the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory 
[Units: Units on a scale]
Mean (Standard Deviation)
 35.1  (20.3)   41.0  (14.81) 

No statistical analysis provided for Functional Performance Assessed by the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory



4.  Secondary:   Global Severity of Dementia Using the CDR Sum of Boxes   [ Time Frame: 24 months ]

Measure Type Secondary
Measure Title Global Severity of Dementia Using the CDR Sum of Boxes
Measure Description Clinical Dementia Rating, Sum of Boxes (CDR-SOB) is a global rating of dementia severity based on the clinician's interpretation of the history and examination. The range of this instrument is 0 to 18 with higher numbers indicating greater impairment.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Global Severity of Dementia Using the CDR Sum of Boxes 
[Units: Units on a scale]
Mean (Standard Deviation)
 12.0  (4.1)   11.5  (3.7) 

No statistical analysis provided for Global Severity of Dementia Using the CDR Sum of Boxes



5.  Secondary:   Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version   [ Time Frame: 24 months ]

Measure Type Secondary
Measure Title Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version
Measure Description The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item caregiver rating questionnaire for the assessment of agitation in older persons. It includes descriptions of 29 agitated behaviors, each rated on a 7-point scale of frequency. The range of this instrument is 29 to 203 with higher numbers indicating greater impairment.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version 
[Units: Units on a scale]
Mean (Standard Deviation)
 10.6  (11.6)   12.1  (10.9) 

No statistical analysis provided for Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version



6.  Secondary:   Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)   [ Time Frame: 24 months ]

Measure Type Secondary
Measure Title Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)
Measure Description ADCS-Clinical Global Impression of Change (ADCS-CGIC) provides a means to reliably assess global change from baseline. It provides a semi-structured format to allow clinicians to gather necessary clinical information from both the participant and informant, in order to make an overall impression of clinical change. The range of this instrument is 1 to 7 with lower numbers indicating improvement and higher numbers indicating a worsened state.
Time Frame 24 months  
Safety Issue No  

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
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Measured Values
   Valproate   Placebo 
Participants Analyzed 
[Units: Participants]
 153   160 
Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC) 
[Units: Units on a scale]
Mean (Standard Deviation)
 5.7  (0.9)   5.5  (1.1) 

No statistical analysis provided for Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)




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

Reporting Groups
  Description
Valproate 250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Placebo Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Serious Adverse Events
    Valproate   Placebo
Total, serious adverse events     
# participants affected / at risk   51/153 (33.33%)   62/160 (38.75%) 
Blood and lymphatic system disorders     
Anaemia     
# participants affected / at risk   1/153 (0.65%)   2/160 (1.25%) 
# events   1   2 
Cardiac disorders     
Angina pectoris     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Angina unstable     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Atrial fibrillation     
# participants affected / at risk   3/153 (1.96%)   1/160 (0.63%) 
# events   4   2 
Bradycardia     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Cardiac disorder     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Cardiac failure     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Cardiac failure congestive     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   2 
Myocardial infarction     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Sinus tachycardia     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Endocrine disorders     
Hypothyroidism     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Gastrointestinal disorders     
Abdominal distension     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Abdominal pain     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Dysphagia     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Faecaloma     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Femoral hernia     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Gastric haemorrhage     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Gastric ulcer haemorrhage     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Gastrointestinal haemorrhage     
# participants affected / at risk   0/153 (0.00%)   2/160 (1.25%) 
# events   0   2 
Oesophageal obstruction     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Rectal haemorrhage     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
General disorders     
Chest pain     
# participants affected / at risk   3/153 (1.96%)   1/160 (0.63%) 
# events   3   1 
Death     
# participants affected / at risk   5/153 (3.27%)   7/160 (4.38%) 
# events   5   7 
Pyrexia     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Hepatobiliary disorders     
Cholecystitis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Hepatic mass     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Infections and infestations     
Bronchitis     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Cellulitis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Enterococcal bacteraemia     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Infection     
# participants affected / at risk   0/153 (0.00%)   2/160 (1.25%) 
# events   0   2 
Influenza     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Kidney infection     
# participants affected / at risk   2/153 (1.31%)   0/160 (0.00%) 
# events   2   0 
Listeriosis     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Nasopharyngitis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Pneumonia     
# participants affected / at risk   5/153 (3.27%)   6/160 (3.75%) 
# events   5   6 
Pneumonia bacterial     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Postoperative infection     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Urinary tract infection     
# participants affected / at risk   4/153 (2.61%)   3/160 (1.88%) 
# events   5   3 
Injury, poisoning and procedural complications     
Accidental overdose     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Drug toxicity     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Fall     
# participants affected / at risk   6/153 (3.92%)   9/160 (5.63%) 
# events   6   10 
Fractured sacrum     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Head injury     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Hip fracture     
# participants affected / at risk   0/153 (0.00%)   2/160 (1.25%) 
# events   0   2 
Joint dislocation     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Subdural haematoma     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   2   0 
Upper limb fracture     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Investigations     
Liver function test abnormal     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Metabolism and nutrition disorders     
Decreased appetite     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Dehydration     
# participants affected / at risk   3/153 (1.96%)   0/160 (0.00%) 
# events   3   0 
Hypoglycaemia     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Hypokalaemia     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Musculoskeletal and connective tissue disorders     
Arthralgia     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Arthritis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Chondropathy     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Muscular weakness     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Musculoskeletal chest pain     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Spondylolisthesis     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Colon cancer     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Mantle cell lymphoma     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Metastatic neoplasm     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Prostate cancer     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Rectal cancer     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Nervous system disorders     
Cerebral artery occlusion     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Cerebral infarction     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Cerebrovascular accident     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Convulsion     
# participants affected / at risk   0/153 (0.00%)   4/160 (2.50%) 
# events   0   4 
Coordination abnormal     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Depressed level of consciousness     
# participants affected / at risk   1/153 (0.65%)   1/160 (0.63%) 
# events   1   1 
Dizziness     
# participants affected / at risk   2/153 (1.31%)   1/160 (0.63%) 
# events   2   1 
Loss of consciousness     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Lumbar radiculopathy     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Subdural haematoma     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Subdural haemorrhage     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Syncope     
# participants affected / at risk   4/153 (2.61%)   2/160 (1.25%) 
# events   4   2 
Transient ischaemic attack     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Psychiatric disorders     
Abnormal behaviour     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Agitation     
# participants affected / at risk   0/153 (0.00%)   2/160 (1.25%) 
# events   0   2 
Confusional state     
# participants affected / at risk   2/153 (1.31%)   0/160 (0.00%) 
# events   2   0 
Delirium     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Hallucination     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Lethargy     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Mental disorder     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Renal and urinary disorders     
Haematuria     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Urinary incontinence     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Urinary retention     
# participants affected / at risk   1/153 (0.65%)   1/160 (0.63%) 
# events   1   1 
Reproductive system and breast disorders     
Breast swelling     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea     
# participants affected / at risk   1/153 (0.65%)   3/160 (1.88%) 
# events   1   3 
Pneumonia aspiration     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Pulmonary embolism     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Respiratory distress     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Skin and subcutaneous tissue disorders     
Hyperhidrosis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Skin ulcer     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Surgical and medical procedures     
Bladder repair     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Breast reconstruction     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Cardiac pacemaker replacement     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Cholecystectomy     
# participants affected / at risk   1/153 (0.65%)   1/160 (0.63%) 
# events   1   1 
Gallbladder operation     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Hip arthroplasty     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Hospitalisation     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Joint arthroplasty     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Knee operation     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Leg amputation     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Lesion excision     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Surgery     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   1   0 
Uterine prolapse repair     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Ventriculo-peritoneal shunt     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Whole blood transfusion     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Vascular disorders     
Deep vein thrombosis     
# participants affected / at risk   1/153 (0.65%)   0/160 (0.00%) 
# events   2   0 
Hypertension     
# participants affected / at risk   1/153 (0.65%)   1/160 (0.63%) 
# events   1   1 
Hypotension     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Pulmonary embolism     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
Thrombosis     
# participants affected / at risk   0/153 (0.00%)   1/160 (0.63%) 
# events   0   1 
1 Term from vocabulary, MedDRA (8.0)




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