Interventional Management of Stroke (IMS) III Trial (IMSIII)

This study has been terminated.
(NINDS/NIH-DSMB recommended halting trial due to futility, no safety concerns.)
Sponsor:
Collaborators:
Medical University of South Carolina
University of Calgary
Information provided by (Responsible Party):
Joseph Broderick, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00359424
First received: July 31, 2006
Last updated: November 19, 2013
Last verified: November 2013
Results First Received: July 4, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Stroke
Interventions: Drug: IV rt-PA alone
Other: endovascular therapy

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

A total of 656 participants underwent randomization

  • participants to endovascular therapy >> and 222 to intravenous t-PA alone) at 58 study >> centers between August 25, 2006, and April 17, >> 2012 in the United States (41 sites), Canada (7), >> Australia (4), and Europe (6)

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
Endovascular Therapy Endovascular therapy (group two) received a lower dose (0.09mg per kg bolus and 0.54mg/kilogram infusion over 40 minutes, maximum dose 53.6mg) or after Amendment #5, a standard dose of IV rt-PA (.9mg/kg with 10% as a bolus and the remainder over one hour) and then underwent an angiogram test (cerebral angiography) right after the medicine was given to check for blood clots. If a clot was not seen, then no more treatment was given. If a clot was seen, the neurointerventionalist chose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that would be most effective in reopening the blocked artery.
IV Rt-PA Alone IV rt-PA alone (group one) received the standard dose (.9mg per kilogram with 10% as a bolus and the remainder as an infusion over 1 hour -maximum dose 90mg) of intravenous (IV) rt-PA alone.

Participant Flow:   Overall Study
    Endovascular Therapy     IV Rt-PA Alone  
STARTED     434     222  
90 Day Follow up     343     172  
180 Day Follow up     325     167  
270 Day Follow up     313     159  
COMPLETED     304     155  
NOT COMPLETED     130     67  
Death                 99                 58  
Lost to Follow-up                 19                 7  
Withdrawal by Subject                 10                 2  
follow up not conducted                 2                 0  



  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.
A sample of 900 was calculated to provide an effect size of 10 percentage points assuming that 40% of the patients had a good outcome in the IV t-PA group, as noted in patients in the NINDS rt-PA Stroke Study who had age and baseline stroke severity similar to the eligibility criteria for the IMS3 trial. The trial was halted at 656 subjects.

Reporting Groups
  Description
Endovascular Therapy Group two will receive a lower dose or a standard dose of IV rt-PA and then undergo an angiogram test (cerebral angiography) right after the medicine is given to check for blood clots. If a clot is not seen then no more treatment will be given. If a clot is seen, the neurointerventionalist will then choose (based on the location and extent of the blood clot) a protocol approved endovascular treatment given directly in the brain artery that will be most effective in reopening the blocked artery.
IV Rt-PA Alone Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.
Total Total of all reporting groups

Baseline Measures
    Endovascular Therapy     IV Rt-PA Alone     Total  
Number of Participants  
[units: participants]
  434     222     656  
Age  
[units: years]
Median ( Full Range )
  69  
  ( 23 to 89 )  
  68  
  ( 23 to 84 )  
  69  
  ( 23 to 89 )  
Gender  
[units: participants]
     
Female     216     100     316  
Male     218     122     340  
NIHSS Score [1]
[units: Score on a scale]
Median ( Full Range )
  17  
  ( 7 to 40 )  
  16  
  ( 8 to 30 )  
  17  
  ( 7 to 40 )  
Time from stroke onset to initiation of IV rt-PA [2]
[units: minutes]
Mean ± Standard Deviation
  122.4  ± 33.7     121.2  ± 33.8     122.0  ± 33.7  
NIHSS Score Strata  
[units: participants]
     
NIHSS Score <20     302     150     452  
NIHSS Score > = 20     132     72     204  
[1]

The National Institutes of Health Stroke Scale (NIHSS), a serial measure of neurologic deficit, is a 42-point scale that >> quantifies neurologic deficits in 11 categories, with 0 indicating normal function without neurologic deficit and higher

>> scores indicating greater severity of deficit.

[2] Time from stroke onset to initiation of intravenous (IV) rt-PA in minutes.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2.   [ Time Frame: at 90 days post randomization ]

2.  Primary:   Death Due to Any Cause   [ Time Frame: within 90 days post randomization ]

3.  Primary:   Symptomatic Intracranial Hemorrhage   [ Time Frame: within the first 30 hours post IV rt-PA ]

4.  Secondary:   Incidence of Parenchymal Type II (PH2) Hematomas   [ Time Frame: within 30 hours post IV rt-PA ]

5.  Secondary:   Asymptomatic Intracranial Hemorrhage   [ Time Frame: within 30 hours post IV rt-PA ]

6.  Secondary:   National Institutes of Health Stroke Scale Score (NIHSS) >> Dichotomized 0-1 Versus 2 or Greater.   [ Time Frame: at 24 hours post randomization ]

7.  Secondary:   National Institutes of Health Stroke Scale Score (NIHSS) Dichotomized 0-1 Versus 2 or Greater.   [ Time Frame: at 90 days post randomization ]

8.  Secondary:   Barthel Index (BI) Dichotomized 0-90 Versus 95-100   [ Time Frame: at 90 days post randomization ]

9.  Secondary:   Trail Making Test Part A Time   [ Time Frame: 90 days post randomization ]

10.  Secondary:   Trail Making Test Part B Time   [ Time Frame: at 90 days post randomization ]

11.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: at 180 days ]

12.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: 270 days ]

13.  Secondary:   Modified Rankin Scale (mRS) Score Dichotomized to 0-2 Versus Greater Than 2   [ Time Frame: 360 days post randomization ]


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   0%  

Reporting Groups
  Description
Endovascular Group two will receive a lower dose or a standard dose of IV rt-PA and then undergo an angiogram test (cerebral angiography) rightafter the medicine is given to check for blood clots. If a clot is not seenthen no more treatment will be given. If a clot is seen, theneurointerventionalist will then choose (based on the location andextent of the blood clot) a protocol approved endovascular treatmentgiven directly in the brain artery that will be most effective inreopening the blocked artery.
IV Only Group one will receive the standard dose of intravenous (IV) rt-PA alone given over an hour.

Other Adverse Events
    Endovascular     IV Only  
Total, other (not including serious) adverse events      
# participants affected / at risk     385/434     202/222  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     39/434 (8.99%)     16/222 (7.21%)  
# events     41     17  
Coagulopathy † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Haemorrhagic disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hilar lymphadenopathy † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Iron deficiency anaemia † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Leukocytosis † 1    
# participants affected / at risk     7/434 (1.61%)     5/222 (2.25%)  
# events     7     5  
Lymphadenopathy † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Lymphadenopathy mediastinal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Pernicious anaemia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Splenic infarction † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Thrombocytopenia † 1    
# participants affected / at risk     5/434 (1.15%)     5/222 (2.25%)  
# events     5     5  
Cardiac disorders      
Acute myocardial infarction † 1    
# participants affected / at risk     4/434 (0.92%)     0/222 (0.00%)  
# events     4     0  
Angina pectoris † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Aortic valve disease † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Aortic valve stenosis † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Arrhythmia † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Arrhythmia supraventricular † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Atrial fibrillation † 1    
# participants affected / at risk     37/434 (8.53%)     21/222 (9.46%)  
# events     41     22  
Atrial flutter † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     4     1  
Atrioventricular block † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Bradycardia † 1    
# participants affected / at risk     18/434 (4.15%)     9/222 (4.05%)  
# events     19     9  
Bundle branch block right † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiac disorder † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Cardiac failure † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Cardiac failure acute † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiac failure congestive † 1    
# participants affected / at risk     16/434 (3.69%)     7/222 (3.15%)  
# events     17     8  
Cardiac valve disease † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Cardiac valve vegetation † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiogenic shock † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiomegaly † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Cardiomyopathy † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Cardiovascular disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Coronary artery disease † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Diastolic dysfunction † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Intracardiac thrombus † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Ischaemic cardiomyopathy † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Mitral valve stenosis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Myocardial infarction † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Myocardial ischaemia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Nodal arrhythmia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Palpitations † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Sick sinus syndrome † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Sinus arrhythmia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Sinus bradycardia † 1    
# participants affected / at risk     2/434 (0.46%)     7/222 (3.15%)  
# events     2     7  
Sinus tachycardia † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Supraventricular tachycardia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Tachycardia † 1    
# participants affected / at risk     15/434 (3.46%)     9/222 (4.05%)  
# events     16     9  
Ventricular arrhythmia † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Ventricular extrasystoles † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Ventricular tachycardia † 1    
# participants affected / at risk     6/434 (1.38%)     3/222 (1.35%)  
# events     6     3  
Congenital, familial and genetic disorders      
Atrial septal defect † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     3     2  
Congenital cystic kidney disease † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Homocystinaemia † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Ear and labyrinth disorders      
Cerumen impaction † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Deafness † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Ear pain † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Vertigo † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Endocrine disorders      
Diabetes insipidus † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hypothyroidism † 1    
# participants affected / at risk     1/434 (0.23%)     3/222 (1.35%)  
# events     1     3  
Eye disorders      
Conjunctival haemorrhage † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Conjunctivitis † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Dry eye † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Eye disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Eye pain † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     2     2  
Eye swelling † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Eyelid oedema † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Eyelid ptosis † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     3     0  
Ocular hyperaemia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Pupil fixed † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Scleral oedema † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Ulcerative keratitis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Vision blurred † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Gastrointestinal disorders      
Abdominal discomfort † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Abdominal distension † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Abdominal pain † 1    
# participants affected / at risk     8/434 (1.84%)     2/222 (0.90%)  
# events     8     2  
Abdominal pain upper † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Abnormal faeces † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Anal haemorrhage † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Ascites † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Bowel movement irregularity † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Constipation † 1    
# participants affected / at risk     41/434 (9.45%)     26/222 (11.71%)  
# events     43     27  
Diarrhoea † 1    
# participants affected / at risk     21/434 (4.84%)     9/222 (4.05%)  
# events     21     9  
Dyspepsia † 1    
# participants affected / at risk     8/434 (1.84%)     4/222 (1.80%)  
# events     8     4  
Dysphagia † 1    
# participants affected / at risk     14/434 (3.23%)     3/222 (1.35%)  
# events     14     3  
Faecal incontinence † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Flatulence † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Food poisoning † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Gastritis † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Gastritis haemorrhagic † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Gastrointestinal haemorrhage † 1    
# participants affected / at risk     5/434 (1.15%)     3/222 (1.35%)  
# events     5     3  
Gastrooesophageal reflux disease † 1    
# participants affected / at risk     6/434 (1.38%)     2/222 (0.90%)  
# events     6     2  
Gingival bleeding † 1    
# participants affected / at risk     3/434 (0.69%)     6/222 (2.70%)  
# events     3     6  
Gingivitis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Haematemesis † 1    
# participants affected / at risk     4/434 (0.92%)     2/222 (0.90%)  
# events     4     2  
Haematochezia † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Haemorrhoids † 1    
# participants affected / at risk     5/434 (1.15%)     1/222 (0.45%)  
# events     5     1  
Hiatus hernia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hypoaesthesia oral † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Ileus † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Impaired gastric emptying † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Inguinal hernia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Loose tooth † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Melaena † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Mouth haemorrhage † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Nausea † 1    
# participants affected / at risk     43/434 (9.91%)     17/222 (7.66%)  
# events     45     18  
Oesophageal stenosis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Periproctitis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Rectal haemorrhage † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Retroperitoneal haematoma † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Salivary hypersecretion † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Stomach discomfort † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Swollen tongue † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Tongue haemorrhage † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Tongue ulceration † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Toothache † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Vomiting † 1    
# participants affected / at risk     39/434 (8.99%)     21/222 (9.46%)  
# events     40     22  
General disorders      
Adverse drug reaction † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Asthenia † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Catheter site bruise † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Catheter site haemorrhage † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Catheter site related reaction † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Chest discomfort † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Chest pain † 1    
# participants affected / at risk     17/434 (3.92%)     9/222 (4.05%)  
# events     17     10  
Chills † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Discomfort † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Extravasation † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Face oedema † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Facial pain † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Fatigue † 1    
# participants affected / at risk     10/434 (2.30%)     2/222 (0.90%)  
# events     10     2  
Feeling cold † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Generalised oedema † 1    
# participants affected / at risk     4/434 (0.92%)     3/222 (1.35%)  
# events     4     3  
Hyperthermia † 1    
# participants affected / at risk     0/434 (0.00%)     2/222 (0.90%)  
# events     0     2  
Implant site pain † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Infusion site erythema † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     2     0  
Infusion site haemorrhage † 1    
# participants affected / at risk     4/434 (0.92%)     3/222 (1.35%)  
# events     4     3  
Infusion site oedema † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Injection site extravasation † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Local swelling † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Malaise † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Mass † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Non-cardiac chest pain † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Oedema peripheral † 1    
# participants affected / at risk     23/434 (5.30%)     13/222 (5.86%)  
# events     29     15  
Pain † 1    
# participants affected / at risk     30/434 (6.91%)     14/222 (6.31%)  
# events     32     16  
Pitting oedema † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Puncture site haemorrhage † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Pyrexia † 1    
# participants affected / at risk     35/434 (8.06%)     31/222 (13.96%)  
# events     36     32  
Swelling † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Systemic inflammatory response syndrome † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Vessel puncture site bruise † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Vessel puncture site haematoma † 1    
# participants affected / at risk     15/434 (3.46%)     1/222 (0.45%)  
# events     15     1  
Vessel puncture site haemorrhage † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Hepatobiliary disorders      
Cholecystitis acute † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hepatomegaly † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Immune system disorders      
Drug hypersensitivity † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hypersensitivity † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Infections and infestations      
Abdominal wall abscess † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Abscess limb † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Bacteraemia † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Bronchitis † 1    
# participants affected / at risk     4/434 (0.92%)     4/222 (1.80%)  
# events     4     4  
Bronchitis acute † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Candidiasis † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Cellulitis † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Chest wall abscess † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Clostridial infection † 1    
# participants affected / at risk     4/434 (0.92%)     3/222 (1.35%)  
# events     4     3  
Clostridium difficile colitis † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Cystitis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Diarrhoea infectious † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Enterococcal infection † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Eye infection † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Fungal infection † 1    
# participants affected / at risk     5/434 (1.15%)     1/222 (0.45%)  
# events     5     1  
Fungal skin infection † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Gastroenteritis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Herpes simplex † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Herpes zoster † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Infusion site infection † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Lobar pneumonia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Lower respiratory tract infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Lymphadenitis bacterial † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Nail infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Nasopharyngitis † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Onychomycosis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Oral candidiasis † 1    
# participants affected / at risk     16/434 (3.69%)     6/222 (2.70%)  
# events     16     6  
Oral fungal infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Orchitis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Pneumonia † 1    
# participants affected / at risk     36/434 (8.29%)     8/222 (3.60%)  
# events     39     8  
Pneumonia staphylococcal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Pneumonia streptococcal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Respiratory tract infection † 1    
# participants affected / at risk     6/434 (1.38%)     1/222 (0.45%)  
# events     6     1  
Sepsis † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Sinusitis † 1    
# participants affected / at risk     7/434 (1.61%)     2/222 (0.90%)  
# events     7     2  
Skin infection † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Staphylococcal bacteraemia † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Staphylococcal infection † 1    
# participants affected / at risk     0/434 (0.00%)     3/222 (1.35%)  
# events     0     3  
Staphylococcal sepsis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Subacute endocarditis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Tooth abscess † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Tracheobronchitis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Upper respiratory tract infection † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Urinary tract infection † 1    
# participants affected / at risk     90/434 (20.74%)     46/222 (20.72%)  
# events     104     51  
Urinary tract infection bacterial † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Urosepsis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Vaginal candidiasis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Vaginal infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Vulvovaginal mycotic infection † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Wound infection † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Wound infection bacterial † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Injury, poisoning and procedural complications      
Alcohol poisoning † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Brain herniation † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Conjunctival abrasion † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Contrast media reaction † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Contusion † 1    
# participants affected / at risk     26/434 (5.99%)     9/222 (4.05%)  
# events     30     12  
Device lead damage † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Difficult to wean from ventilator † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Drug administration error † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Epicondylitis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Excoriation † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     4     2  
Fall † 1    
# participants affected / at risk     13/434 (3.00%)     18/222 (8.11%)  
# events     15     18  
Feeding tube complication † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     2  
Haematuria traumatic † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hand fracture † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Incision site complication † 1    
# participants affected / at risk     5/434 (1.15%)     2/222 (0.90%)  
# events     5     3  
Incision site oedema † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Intubation complication † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Joint dislocation † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Joint sprain † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Laceration † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Medication error † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Mouth injury † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Muscle strain † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Pacemaker complication † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Periorbital haematoma † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Post procedural haematoma † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Post procedural haematuria † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Post procedural haemorrhage † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     1  
Post-traumatic pain † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Procedural complication † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Procedural hypertension † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Renal injury † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Rib fracture † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Skin injury † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Skin laceration † 1    
# participants affected / at risk     8/434 (1.84%)     0/222 (0.00%)  
# events     9     0  
Stress fracture † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Tracheostomy malfunction † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Transfusion reaction † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Traumatic fracture † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Traumatic haematoma † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Upper limb fracture † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Wound † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Wrong technique in drug usage process † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Investigations      
Activated partial thromboplastin time prolonged † 1    
# participants affected / at risk     4/434 (0.92%)     0/222 (0.00%)  
# events     4     0  
Bacteria stool identified † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Blood albumin abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood alkaline phosphatase increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood cholesterol increased † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood creatine phosphokinase increased † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood creatinine increased † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Blood culture positive † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood electrolytes abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood fibrinogen decreased † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood fibrinogen increased † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood glucose abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Blood glucose increased † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Blood lactate dehydrogenase increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood magnesium decreased † 1    
# participants affected / at risk     8/434 (1.84%)     3/222 (1.35%)  
# events     8     3  
Blood phosphorus decreased † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Blood potassium decreased † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Blood pressure decreased † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Blood pressure increased † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Blood test abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood thyroid stimulating hormone decreased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood urea abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Blood urea increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Body temperature increased † 1    
# participants affected / at risk     6/434 (1.38%)     2/222 (0.90%)  
# events     6     3  
Breath sounds abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     3  
C-reactive protein increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiac enzymes increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cardiac stress test abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Chest X-ray abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Computerised tomogram abnormal † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Culture urine positive † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Drug level fluctuating † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Electrocardiogram ST segment abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Electrocardiogram ST segment depression † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Electrocardiogram ST segment elevation † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Electroencephalogram abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Free prostate-specific antigen increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Full blood count abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Haematocrit decreased † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Haematology test abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Haemoglobin † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Haemoglobin abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Haemoglobin decreased † 1    
# participants affected / at risk     8/434 (1.84%)     2/222 (0.90%)  
# events     9     2  
Heart rate decreased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Inspiratory capacity decreased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
International normalised ratio increased † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Myoglobin blood increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
NIH stroke scale score increased † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Neurological examination abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Oxygen saturation decreased † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Platelet count decreased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Platelet count increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Prothrombin time prolonged † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Pulmonary function test decreased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Red blood cell count decreased † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Red blood cell sedimentation rate increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Residual urine volume † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Scan with contrast abnormal † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Troponin I increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Troponin increased † 1    
# participants affected / at risk     10/434 (2.30%)     3/222 (1.35%)  
# events     10     3  
Urine output decreased † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Urine output increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Venous pressure jugular increased † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Weight decreased † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Weight increased † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
White blood cell count increased † 1    
# participants affected / at risk     13/434 (3.00%)     3/222 (1.35%)  
# events     13     3  
Metabolism and nutrition disorders      
Anorexia † 1    
# participants affected / at risk     1/434 (0.23%)     2/222 (0.90%)  
# events     1     2  
Appetite disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Dehydration † 1    
# participants affected / at risk     5/434 (1.15%)     3/222 (1.35%)  
# events     5     3  
Diabetes mellitus † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     3     2  
Diabetes mellitus non-insulin-dependent † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Electrolyte imbalance † 1    
# participants affected / at risk     23/434 (5.30%)     7/222 (3.15%)  
# events     25     7  
Fluid imbalance † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Fluid overload † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Fluid retention † 1    
# participants affected / at risk     0/434 (0.00%)     2/222 (0.90%)  
# events     0     2  
Gout † 1    
# participants affected / at risk     3/434 (0.69%)     3/222 (1.35%)  
# events     3     3  
Hyperammonaemia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hyperchloraemia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hypercholesterolaemia † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Hyperglycaemia † 1    
# participants affected / at risk     31/434 (7.14%)     11/222 (4.95%)  
# events     31     11  
Hyperhomocysteinaemia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Hyperkalaemia † 1    
# participants affected / at risk     2/434 (0.46%)     2/222 (0.90%)  
# events     2     2  
Hyperlipidaemia † 1    
# participants affected / at risk     5/434 (1.15%)     10/222 (4.50%)  
# events     5     10  
Hypernatraemia † 1    
# participants affected / at risk     3/434 (0.69%)     3/222 (1.35%)  
# events     3     3  
Hypoalbuminaemia † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Hypocalcaemia † 1    
# participants affected / at risk     8/434 (1.84%)     1/222 (0.45%)  
# events     8     1  
Hypoglycaemia † 1    
# participants affected / at risk     5/434 (1.15%)     1/222 (0.45%)  
# events     5     1  
Hypokalaemia † 1    
# participants affected / at risk     40/434 (9.22%)     18/222 (8.11%)  
# events     40     20  
Hypomagnesaemia † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Hyponatraemia † 1    
# participants affected / at risk     14/434 (3.23%)     7/222 (3.15%)  
# events     14     7  
Hypophosphataemia † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Hypovolaemia † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Lactose intolerance † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Malnutrition † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     3     2  
Metabolic acidosis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Metabolic alkalosis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Vitamin D deficiency † 1    
# participants affected / at risk     5/434 (1.15%)     5/222 (2.25%)  
# events     5     5  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     22/434 (5.07%)     7/222 (3.15%)  
# events     25     7  
Back pain † 1    
# participants affected / at risk     23/434 (5.30%)     13/222 (5.86%)  
# events     24     13  
Buttock pain † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Flank pain † 1    
# participants affected / at risk     4/434 (0.92%)     0/222 (0.00%)  
# events     4     0  
Groin pain † 1    
# participants affected / at risk     4/434 (0.92%)     2/222 (0.90%)  
# events     4     2  
Haemarthrosis † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Joint effusion † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Joint swelling † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Limb discomfort † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Monarthritis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Muscle haemorrhage † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Muscle spasms † 1    
# participants affected / at risk     1/434 (0.23%)     5/222 (2.25%)  
# events     1     6  
Muscle twitching † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Muscular weakness † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Musculoskeletal chest pain † 1    
# participants affected / at risk     2/434 (0.46%)     3/222 (1.35%)  
# events     2     3  
Musculoskeletal disorder † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Musculoskeletal pain † 1    
# participants affected / at risk     18/434 (4.15%)     8/222 (3.60%)  
# events     18     8  
Musculoskeletal stiffness † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Myalgia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Neck pain † 1    
# participants affected / at risk     7/434 (1.61%)     5/222 (2.25%)  
# events     7     5  
Pain in extremity † 1    
# participants affected / at risk     28/434 (6.45%)     12/222 (5.41%)  
# events     31     17  
Pain in jaw † 1    
# participants affected / at risk     4/434 (0.92%)     0/222 (0.00%)  
# events     4     0  
Periarthritis † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Rheumatoid arthritis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Rotator cuff syndrome † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Sacral pain † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Spinal disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Trigger finger † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Chondromatosis † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Colon cancer recurrent † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Thyroid neoplasm † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Nervous system disorders      
Amnesia † 1    
# participants affected / at risk     3/434 (0.69%)     0/222 (0.00%)  
# events     3     0  
Aphasia † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Balance disorder † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Brain oedema † 1    
# participants affected / at risk     10/434 (2.30%)     15/222 (6.76%)  
# events     10     16  
Carotid arterial embolus † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Carotid artery dissection † 1    
# participants affected / at risk     7/434 (1.61%)     0/222 (0.00%)  
# events     8     0  
Carotid artery stenosis † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Cerebellar haemorrhage † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Cerebral artery embolism † 1    
# participants affected / at risk     5/434 (1.15%)     0/222 (0.00%)  
# events     5     0  
Cerebral haemorrhage † 1    
# participants affected / at risk     26/434 (5.99%)     7/222 (3.15%)  
# events     26     7  
Cerebral infarction † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Cerebrovascular accident † 1    
# participants affected / at risk     4/434 (0.92%)     1/222 (0.45%)  
# events     4     2  
Cerebrovascular spasm † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Cognitive disorder † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Complex regional pain syndrome † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Convulsion † 1    
# participants affected / at risk     16/434 (3.69%)     5/222 (2.25%)  
# events     19     5  
Coordination abnormal † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Depressed level of consciousness † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Disturbance in attention † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Dizziness † 1    
# participants affected / at risk     15/434 (3.46%)     1/222 (0.45%)  
# events     17     1  
Dysgeusia † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Dystonia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Encephalomalacia † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Encephalopathy † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Facial palsy † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Grand mal convulsion † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Haemorrhage intracranial † 1    
# participants affected / at risk     43/434 (9.91%)     14/222 (6.31%)  
# events     43     14  
Haemorrhagic cerebral infarction † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Haemorrhagic stroke † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Haemorrhagic transformation stroke † 1    
# participants affected / at risk     35/434 (8.06%)     18/222 (8.11%)  
# events     35     18  
Headache † 1    
# participants affected / at risk     80/434 (18.43%)     51/222 (22.97%)  
# events     86     55  
Hemiparesis † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Hydrocephalus † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Hypoaesthesia † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     4     2  
Intention tremor † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Intracranial aneurysm † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Intracranial haematoma † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Intraventricular haemorrhage † 1    
# participants affected / at risk     2/434 (0.46%)     0/222 (0.00%)  
# events     2     0  
Lethargy † 1    
# participants affected / at risk     5/434 (1.15%)     5/222 (2.25%)  
# events     6     5  
Loss of consciousness † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Mental impairment † 1    
# participants affected / at risk     2/434 (0.46%)     1/222 (0.45%)  
# events     2     1  
Muscle spasticity † 1    
# participants affected / at risk     3/434 (0.69%)     2/222 (0.90%)  
# events     3     2  
Neurological symptom † 1    
# participants affected / at risk     12/434 (2.76%)     5/222 (2.25%)  
# events     12     5  
Neuropathy † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Paraesthesia † 1    
# participants affected / at risk     5/434 (1.15%)     0/222 (0.00%)  
# events     5     0  
Partial seizures † 1    
# participants affected / at risk     3/434 (0.69%)     1/222 (0.45%)  
# events     3     1  
Presyncope † 1    
# participants affected / at risk     1/434 (0.23%)     1/222 (0.45%)  
# events     1     1  
Putamen haemorrhage † 1    
# participants affected / at risk     0/434 (0.00%)     1/222 (0.45%)  
# events     0     1  
Restless legs syndrome † 1    
# participants affected / at risk     1/434 (0.23%)     0/222 (0.00%)  
# events     1     0  
Sciatica † 1    
# participants affected / at risk