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Trial to Evaluate the Efficacy of GSK Biologicals' Influenza Vaccine GSK2186877A in Adults 65 Year of Age and Older

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00753272
First received: September 12, 2008
Last updated: September 20, 2016
Last verified: September 2016
Results First Received: April 26, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition: Influenza
Interventions: Biological: GSK Bio's influenza vaccine GSK2186877A
Biological: Fluarix TM

  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
Subjects were vaccinated during the pre-influenza season at Day 0, were contacted by phone during the surveillance period from mid November to the end of the influenza season (April-May) and were contacted by phone at Days 270 and 365 for the Year 1 influenza season 2008/2009 and the Year 2 influenza season 2009/2010.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
For lot-to-lot consistency analyses after Dose 1 at Day 0 of the Year 1, FluNG Group was divided in 3 sub-groups: FluNG Lot 1 Group, FluNG Lot 2 Group and FluNG Lot 3 Group: subjects received 1 dose of FluNG vaccine Lot 1, 2 or 3 at Day 0 of the Year 1. They all received Dose 2 at Day 0 of the Year 2, again from 3 different lots.

Reporting Groups
  Description
FluNG Group subjects received 2 doses (1 dose per season) of FluNG vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).
Fluarix Group subjects received 2 doses (1 dose per season) of Fluarix™ vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).

Participant Flow:   Overall Study
    FluNG Group   Fluarix Group
STARTED   21893   21802 
COMPLETED   16911   16895 
NOT COMPLETED   4982   4907 
Adverse Event                878                869 
Protocol Violation                28                46 
Withdrawal by Subject                2481                2407 
Lost to Follow-up                491                497 
Unspecified                1104                1088 



  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
FluNG Group subjects received 2 doses (1 dose per season) of FluNG vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).
Fluarix Group subjects received 2 doses (1 dose per season) of Fluarix™ vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).
Total Total of all reporting groups

Baseline Measures
   FluNG Group   Fluarix Group   Total 
Overall Participants Analyzed 
[Units: Participants]
 21893   21802   43695 
Age 
[Units: Years]
Mean (Standard Deviation)
     
Years   73.5  (6.09)   73.5  (6.16)   73.5  (6.13) 
Gender 
[Units: Subjects]
     
Female   12549   12422   24971 
Male   9344   9380   18724 


  Outcome Measures
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1.  Primary:   Number of Subjects Reporting Polymerase Chain Reaction (PCR)-Confirmed Influenza A and/or B Infection.   [ Time Frame: After the first dose during the corresponding surveillance period (from mid November 2008 to the end of April 2009 (end of influenza season)) ]

2.  Primary:   Serum Hemagglutination-inhibition (HI) Antibody Titers, Against Each of the 3 Vaccine Influenza Strains, in the FluNG Groups.   [ Time Frame: At Days 0 (pre-vaccination Dose 1) and 21 (post-vaccination Dose 1) of the first year (2008/2009) of the study ]

3.  Secondary:   Number of Subjects Reporting Polymerase Chain Reaction (PCR)-Confirmed Influenza A and/or B Infection.   [ Time Frame: During the whole surveillance period (from mid November 2008 to end of April 2009 and from mid November 2009 to end of April 2010) ]

4.  Secondary:   Number of Subjects Reporting Culture-confirmed Influenza A and/or B Infection.   [ Time Frame: During the whole surveillance period (from mid November 2008 to end of April 2009 and from mid November 2009 to end of April 2010) ]

5.  Secondary:   Number of Subjects Reporting Pneumonia or Clinical Influenza After the First Dose of Vaccine.   [ Time Frame: During the influenza peak season within the first surveillance period (the influenza peak season being defined per country, falling somewhere between mid November 2008 to end of April 2009) ]

6.  Secondary:   Number of Subjects Reporting All-cause Death After the First Dose of Vaccine.   [ Time Frame: During the influenza peak season within the first surveillance period (the influenza peak season being defined per country, falling somewhere between mid November 2008 to end of April 2009) ]

7.  Secondary:   Number of Subjects Reporting Hospitalization Due to Respiratory Diseases After the First Dose of Vaccine   [ Time Frame: During the influenza peak season within the first surveillance period (the influenza peak season being defined per country, falling somewhere between mid November 2008 to end of April 2009) ]

8.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Adverse Events (AEs) of Specific Interest Including Autoimmune Disease (AID).   [ Time Frame: Within 365 days after the first dose (from Dose 1 at Day 0 up to Day 365 for the Year 2008/2009) ]

9.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Adverse Events (AEs) of Specific Interest Including Autoimmune Disease (AID).   [ Time Frame: Within 365 days after the second dose (from Dose 1 at Day 0 up to Day 365 for the Year 2009/2010) ]

10.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Adverse Events (AEs) of Specific Interest Including Autoimmune Disease (AID).   [ Time Frame: During the entire study period (during the 365 days of follow-up after each vaccination at Year 2008/2009 and Year 2009/2010) ]

11.  Secondary:   Number of Subjects Reporting Any and Related to Vaccination Serious Adverse Events (SAEs).   [ Time Frame: During the entire study period (during the 365 days of follow-up after each vaccination at Year 2008/2009 and Year 2009/2010) ]

12.  Secondary:   Number of Subjects Reporting Any and Severe (Grade 3) Solicited Local Symptoms.   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the first year (2008/2009) ]

13.  Secondary:   Number of Days With Any Grade of Solicited Local Symptoms   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the first year (2008/2009) ]

14.  Secondary:   Number of Subjects Reporting Any and Severe (Grade 3) Solicited Local Symptoms   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the second year (2009/2010) ]

15.  Secondary:   Number of Days With Any Grade of Solicited Local Symptoms.   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the second year (2009/2010) ]

16.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Solicited General Symptoms   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the first year (2008/2009) ]

17.  Secondary:   Number of Days With Any Grade of Solicited General Symptoms   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the first year (2008/2009) ]

18.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related Solicited General Symptoms.   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the second year (2009/2010) ]

19.  Secondary:   Number of Days With Any Grade of Solicited General Symptoms.   [ Time Frame: During the 7-day (Days 0-6) post-vaccination period, the second year (2009/2010) ]

20.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited Adverse Events (AEs).   [ Time Frame: Within 21 days (Days 0-20) after the first dose (Year 2008/2009) ]
  Hide Outcome Measure 20

Measure Type Secondary
Measure Title Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited Adverse Events (AEs).
Measure Description An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Grade 3 = event that prevented normal, everyday activities. Related = event assessed by the investigator as causally related to the study vaccination.
Time Frame Within 21 days (Days 0-20) after the first dose (Year 2008/2009)  
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.
The One-Dose Total Vaccinated cohort for the safety subset included all subjects with at least one vaccine administration documented during the first year of the study and included in the safety subset.

Reporting Groups
  Description
FluNG Group subjects received 2 doses (1 dose per season) of FluNG vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).
Fluarix Group subjects received 2 doses (1 dose per season) of Fluarix™ vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).

Measured Values
   FluNG Group   Fluarix Group 
Participants Analyzed 
[Units: Participants]
 3015   3002 
Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited Adverse Events (AEs). 
[Units: Subjects]
   
Any AEs   428   427 
Grade 3 AEs   48   52 
Related AEs   83   58 

No statistical analysis provided for Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited Adverse Events (AEs).



21.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited Adverse Events (AEs).   [ Time Frame: Within 21 days (Days 0-20) after the second dose (Year 2009/2010) ]

22.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited AEs With Medically Attended Visit   [ Time Frame: Within 180 days (Days 0-179) after the first dose (Year 2008/2009) ]

23.  Secondary:   Number of Subjects Reporting Any, Severe (Grade 3) and Related to Vaccination Unsolicited AEs With Medically Attended Visit.   [ Time Frame: Within 180 days (Days 0-179) after the second dose (Year 2009/2010) ]

24.  Secondary:   Serum Hemagglutination-inhibition (HI) Antibody Titer Against Each of the 3 Vaccine Influenza Strains.   [ Time Frame: At Days 0 (pre-vaccination Dose 1) and 21 (post-vaccination Dose 1) of the first year (2008/2009) of the study ]

25.  Secondary:   Serum Hemagglutination-inhibition (HI) Antibody Titer Against Each of the 3 Vaccine Influenza Strains   [ Time Frame: At Days 0 (pre-vaccination Dose 2) and 21 (post-vaccination Dose 2) of the second year (2009/2010) of the study ]

26.  Secondary:   Serum Hemagglutination-inhibition (HI) Antibody Titer Against Each of the 3 Vaccine Influenza Strains.   [ Time Frame: At Days 0 (pre-vaccination Dose 1), 21 (post-vaccination Dose 1) and 180 (post-vaccination Dose 1) of the first year (2008/2009) of the study ]

27.  Secondary:   Serum Hemagglutination-inhibition (HI) Antibody Titer Against Each of the 3 Vaccine Influenza Strains.   [ Time Frame: At Days 0 (pre-vaccination Dose 2), 21 (post-vaccination Dose 2) and 180 (post-vaccination Dose 2) of the second year (2009/2010) of the study ]

28.  Secondary:   Number of Seroconverted Subjects for HI Antibodies Against Each of the 3 Vaccine Influenza Strains   [ Time Frame: At Day 21 of the first year (2008/2009) of the study. ]


  Serious Adverse Events
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Time Frame Solicited symptoms: During the 7-day post-vaccination period the first year (2008/2009) and the second year (2009/2010). SAEs: During the entire study period (during the 365 days of follow-up after each vaccination at Year 2008/2009 and Year 2009/2010)
Additional Description No text entered.

Reporting Groups
  Description
FluNG Group subjects received 2 doses (1 dose per season) of FluNG vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).
Fluarix Group subjects received 2 doses (1 dose per season) of Fluarix™ vaccine during the Northern Hemisphere (NH) vaccination periods. One dose at Day 0 of the Year 1 and one dose at Day 0 of the Year 2 (= Day 365 Year 1).

Serious Adverse Events
    FluNG Group   Fluarix Group
Total, serious adverse events     
# participants affected / at risk   4071/21893 (18.59%)   4066/21802 (18.65%) 
Blood and lymphatic system disorders     
Anaemia     
# participants affected / at risk   48/21893 (0.22%)   64/21802 (0.29%) 
Iron deficiency anaemia     
# participants affected / at risk   7/21893 (0.03%)   14/21802 (0.06%) 
Haemorrhagic anaemia     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Thrombocytopenia     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Cardiac disorders     
Atrial fibrillation     
# participants affected / at risk   211/21893 (0.96%)   178/21802 (0.82%) 
Myocardial infarction     
# participants affected / at risk   169/21893 (0.77%)   167/21802 (0.77%) 
Cardiac failure congestive     
# participants affected / at risk   147/21893 (0.67%)   153/21802 (0.70%) 
Cardiac failure     
# participants affected / at risk   98/21893 (0.45%)   102/21802 (0.47%) 
Coronary artery disease     
# participants affected / at risk   90/21893 (0.41%)   75/21802 (0.34%) 
Angina pectoris     
# participants affected / at risk   77/21893 (0.35%)   75/21802 (0.34%) 
Myocardial ischaemia     
# participants affected / at risk   64/21893 (0.29%)   62/21802 (0.28%) 
Acute myocardial infarction     
# participants affected / at risk   38/21893 (0.17%)   59/21802 (0.27%) 
Arrhythmia     
# participants affected / at risk   35/21893 (0.16%)   26/21802 (0.12%) 
Cardiac arrest     
# participants affected / at risk   33/21893 (0.15%)   28/21802 (0.13%) 
Bradycardia     
# participants affected / at risk   18/21893 (0.08%)   20/21802 (0.09%) 
Angina unstable     
# participants affected / at risk   17/21893 (0.08%)   18/21802 (0.08%) 
Atrial flutter     
# participants affected / at risk   14/21893 (0.06%)   16/21802 (0.07%) 
Atrioventricular block     
# participants affected / at risk   11/21893 (0.05%)   16/21802 (0.07%) 
Acute coronary syndrome     
# participants affected / at risk   6/21893 (0.03%)   18/21802 (0.08%) 
Mitral valve incompetence     
# participants affected / at risk   14/21893 (0.06%)   10/21802 (0.05%) 
Aortic valve stenosis     
# participants affected / at risk   13/21893 (0.06%)   8/21802 (0.04%) 
Sick sinus syndrome     
# participants affected / at risk   10/21893 (0.05%)   11/21802 (0.05%) 
Atrioventricular block complete     
# participants affected / at risk   9/21893 (0.04%)   11/21802 (0.05%) 
Supraventricular tachycardia     
# participants affected / at risk   7/21893 (0.03%)   13/21802 (0.06%) 
Left ventricular failure     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Tachyarrhythmia     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Coronary artery stenosis     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Arrhythmia supraventricular     
# participants affected / at risk   11/21893 (0.05%)   4/21802 (0.02%) 
Ventricular fibrillation     
# participants affected / at risk   8/21893 (0.04%)   7/21802 (0.03%) 
Cardiopulmonary failure     
# participants affected / at risk   7/21893 (0.03%)   6/21802 (0.03%) 
Arteriosclerosis coronary artery     
# participants affected / at risk   6/21893 (0.03%)   6/21802 (0.03%) 
Cardiac failure chronic     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Cardio-respiratory arrest     
# participants affected / at risk   5/21893 (0.02%)   7/21802 (0.03%) 
Cardiovascular insufficiency     
# participants affected / at risk   6/21893 (0.03%)   6/21802 (0.03%) 
Coronary artery occlusion     
# participants affected / at risk   6/21893 (0.03%)   6/21802 (0.03%) 
Cardiac failure acute     
# participants affected / at risk   6/21893 (0.03%)   5/21802 (0.02%) 
Atrioventricular block second degree     
# participants affected / at risk   8/21893 (0.04%)   2/21802 (0.01%) 
Ventricular tachycardia     
# participants affected / at risk   4/21893 (0.02%)   6/21802 (0.03%) 
Aortic valve incompetence     
# participants affected / at risk   3/21893 (0.01%)   6/21802 (0.03%) 
Cardiogenic shock     
# participants affected / at risk   6/21893 (0.03%)   2/21802 (0.01%) 
Tachycardia     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Ventricular extrasystoles     
# participants affected / at risk   4/21893 (0.02%)   4/21802 (0.02%) 
Coronary artery insufficiency     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Hypertensive heart disease     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Pericarditis     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Congenital, familial and genetic disorders     
Gastrointestinal angiodysplasia     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Ear and labyrinth disorders     
Vertigo     
# participants affected / at risk   14/21893 (0.06%)   19/21802 (0.09%) 
Vestibular disorder     
# participants affected / at risk   5/21893 (0.02%)   8/21802 (0.04%) 
Vertigo positional     
# participants affected / at risk   2/21893 (0.01%)   8/21802 (0.04%) 
Endocrine disorders     
Hypothyroidism     
# participants affected / at risk   4/21893 (0.02%)   7/21802 (0.03%) 
Hyperthyroidism     
# participants affected / at risk   1/21893 (0.00%)   9/21802 (0.04%) 
Goitre     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Eye disorders     
Cataract     
# participants affected / at risk   16/21893 (0.07%)   20/21802 (0.09%) 
Glaucoma     
# participants affected / at risk   3/21893 (0.01%)   8/21802 (0.04%) 
Retinal detachment     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Gastrointestinal disorders     
Inguinal hernia     
# participants affected / at risk   37/21893 (0.17%)   26/21802 (0.12%) 
Gastrointestinal haemorrhage     
# participants affected / at risk   19/21893 (0.09%)   29/21802 (0.13%) 
Gastritis     
# participants affected / at risk   20/21893 (0.09%)   22/21802 (0.10%) 
Pancreatitis acute     
# participants affected / at risk   18/21893 (0.08%)   18/21802 (0.08%) 
Gastric ulcer     
# participants affected / at risk   16/21893 (0.07%)   18/21802 (0.08%) 
Intestinal obstruction     
# participants affected / at risk   15/21893 (0.07%)   19/21802 (0.09%) 
Pancreatitis     
# participants affected / at risk   18/21893 (0.08%)   11/21802 (0.05%) 
Ileus     
# participants affected / at risk   14/21893 (0.06%)   11/21802 (0.05%) 
Small intestinal obstruction     
# participants affected / at risk   13/21893 (0.06%)   12/21802 (0.06%) 
Constipation     
# participants affected / at risk   11/21893 (0.05%)   13/21802 (0.06%) 
Duodenal ulcer     
# participants affected / at risk   15/21893 (0.07%)   8/21802 (0.04%) 
Peritonitis     
# participants affected / at risk   12/21893 (0.05%)   11/21802 (0.05%) 
Colitis     
# participants affected / at risk   8/21893 (0.04%)   14/21802 (0.06%) 
Abdominal pain     
# participants affected / at risk   13/21893 (0.06%)   7/21802 (0.03%) 
Colonic polyp     
# participants affected / at risk   11/21893 (0.05%)   9/21802 (0.04%) 
Upper gastrointestinal haemorrhage     
# participants affected / at risk   11/21893 (0.05%)   9/21802 (0.04%) 
Diarrhoea     
# participants affected / at risk   8/21893 (0.04%)   9/21802 (0.04%) 
Gastritis erosive     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Gastrooesophageal reflux disease     
# participants affected / at risk   7/21893 (0.03%)   10/21802 (0.05%) 
Diverticulum     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Gastric ulcer haemorrhage     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Hiatus hernia     
# participants affected / at risk   5/21893 (0.02%)   11/21802 (0.05%) 
Colitis ischaemic     
# participants affected / at risk   3/21893 (0.01%)   11/21802 (0.05%) 
Large intestine perforation     
# participants affected / at risk   8/21893 (0.04%)   5/21802 (0.02%) 
Dyspepsia     
# participants affected / at risk   4/21893 (0.02%)   8/21802 (0.04%) 
Haemorrhoids     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Rectal haemorrhage     
# participants affected / at risk   5/21893 (0.02%)   7/21802 (0.03%) 
Reflux oesophagitis     
# participants affected / at risk   3/21893 (0.01%)   9/21802 (0.04%) 
Dysphagia     
# participants affected / at risk   3/21893 (0.01%)   7/21802 (0.03%) 
Faecaloma     
# participants affected / at risk   4/21893 (0.02%)   6/21802 (0.03%) 
Lower gastrointestinal haemorrhage     
# participants affected / at risk   2/21893 (0.01%)   8/21802 (0.04%) 
Abdominal hernia     
# participants affected / at risk   6/21893 (0.03%)   3/21802 (0.01%) 
Oesophagitis     
# participants affected / at risk   5/21893 (0.02%)   4/21802 (0.02%) 
Pancreatitis chronic     
# participants affected / at risk   6/21893 (0.03%)   3/21802 (0.01%) 
Umbilical hernia     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Diverticular perforation     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Diverticulum intestinal     
# participants affected / at risk   6/21893 (0.03%)   2/21802 (0.01%) 
Peptic ulcer     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Vomiting     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Duodenitis     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Gastric haemorrhage     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Nausea     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Oesophageal stenosis     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Gastroduodenal ulcer     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Haematochezia     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Ileus paralytic     
# participants affected / at risk   5/21893 (0.02%)   1/21802 (0.00%) 
Intestinal polyp     
# participants affected / at risk   5/21893 (0.02%)   1/21802 (0.00%) 
Oesophageal varices haemorrhage     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
General disorders     
Chest pain     
# participants affected / at risk   42/21893 (0.19%)   45/21802 (0.21%) 
Death     
# participants affected / at risk   28/21893 (0.13%)   27/21802 (0.12%) 
Sudden death     
# participants affected / at risk   34/21893 (0.16%)   18/21802 (0.08%) 
Multi-organ failure     
# participants affected / at risk   9/21893 (0.04%)   15/21802 (0.07%) 
Cardiac death     
# participants affected / at risk   11/21893 (0.05%)   8/21802 (0.04%) 
Sudden cardiac death     
# participants affected / at risk   12/21893 (0.05%)   7/21802 (0.03%) 
Non-cardiac chest pain     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Asthenia     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Pyrexia     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Device dislocation     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Oedema peripheral     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Pain     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Hepatobiliary disorders     
Cholelithiasis     
# participants affected / at risk   44/21893 (0.20%)   45/21802 (0.21%) 
Cholecystitis     
# participants affected / at risk   40/21893 (0.18%)   43/21802 (0.20%) 
Cholecystitis acute     
# participants affected / at risk   23/21893 (0.11%)   17/21802 (0.08%) 
Bile duct stone     
# participants affected / at risk   15/21893 (0.07%)   9/21802 (0.04%) 
Hepatic cirrhosis     
# participants affected / at risk   11/21893 (0.05%)   9/21802 (0.04%) 
Cholangitis     
# participants affected / at risk   5/21893 (0.02%)   5/21802 (0.02%) 
Biliary colic     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Immune system disorders     
Hypersensitivity     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Anaphylactic reaction     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Infections and infestations     
Pneumonia     
# participants affected / at risk   228/21893 (1.04%)   226/21802 (1.04%) 
Urinary tract infection     
# participants affected / at risk   129/21893 (0.59%)   111/21802 (0.51%) 
Sepsis     
# participants affected / at risk   41/21893 (0.19%)   45/21802 (0.21%) 
Gastroenteritis     
# participants affected / at risk   35/21893 (0.16%)   47/21802 (0.22%) 
Diverticulitis     
# participants affected / at risk   31/21893 (0.14%)   34/21802 (0.16%) 
Cellulitis     
# participants affected / at risk   29/21893 (0.13%)   27/21802 (0.12%) 
Bronchopneumonia     
# participants affected / at risk   26/21893 (0.12%)   29/21802 (0.13%) 
Erysipelas     
# participants affected / at risk   28/21893 (0.13%)   21/21802 (0.10%) 
Lobar pneumonia     
# participants affected / at risk   16/21893 (0.07%)   19/21802 (0.09%) 
Pyelonephritis     
# participants affected / at risk   21/21893 (0.10%)   13/21802 (0.06%) 
Appendicitis     
# participants affected / at risk   15/21893 (0.07%)   17/21802 (0.08%) 
Upper respiratory tract infection     
# participants affected / at risk   13/21893 (0.06%)   17/21802 (0.08%) 
Septic shock     
# participants affected / at risk   6/21893 (0.03%)   18/21802 (0.08%) 
Gangrene     
# participants affected / at risk   10/21893 (0.05%)   11/21802 (0.05%) 
Cystitis     
# participants affected / at risk   5/21893 (0.02%)   12/21802 (0.06%) 
Herpes zoster     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Respiratory tract infection     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Wound infection     
# participants affected / at risk   8/21893 (0.04%)   7/21802 (0.03%) 
Staphylococcal infection     
# participants affected / at risk   8/21893 (0.04%)   5/21802 (0.02%) 
Urosepsis     
# participants affected / at risk   8/21893 (0.04%)   4/21802 (0.02%) 
Sinusitis     
# participants affected / at risk   3/21893 (0.01%)   7/21802 (0.03%) 
Osteomyelitis     
# participants affected / at risk   2/21893 (0.01%)   7/21802 (0.03%) 
Clostridial infection     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Clostridium difficile colitis     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Infection     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Candidiasis     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Cholecystitis infective     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Gastroenteritis norovirus     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Gastroenteritis viral     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Escherichia urinary tract infection     
# participants affected / at risk   6/21893 (0.03%)   0/21802 (0.00%) 
Infected skin ulcer     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Infective exacerbation of chronic obstructive airways diseas     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Localised infection     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Lower respiratory tract infection     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Lung infection     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Pharyngitis     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Postoperative wound infection     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Pyelonephritis acute     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Injury, poisoning and procedural complications     
Femoral neck fracture     
# participants affected / at risk   35/21893 (0.16%)   53/21802 (0.24%) 
Femur fracture     
# participants affected / at risk   34/21893 (0.16%)   45/21802 (0.21%) 
Hip fracture     
# participants affected / at risk   23/21893 (0.11%)   34/21802 (0.16%) 
Humerus fracture     
# participants affected / at risk   19/21893 (0.09%)   35/21802 (0.16%) 
Rib fracture     
# participants affected / at risk   21/21893 (0.10%)   14/21802 (0.06%) 
Toxicity to various agents     
# participants affected / at risk   17/21893 (0.08%)   18/21802 (0.08%) 
Radius fracture     
# participants affected / at risk   13/21893 (0.06%)   20/21802 (0.09%) 
Contusion     
# participants affected / at risk   20/21893 (0.09%)   12/21802 (0.06%) 
Ankle fracture     
# participants affected / at risk   14/21893 (0.06%)   15/21802 (0.07%) 
Concussion     
# participants affected / at risk   10/21893 (0.05%)   16/21802 (0.07%) 
Upper limb fracture     
# participants affected / at risk   9/21893 (0.04%)   17/21802 (0.08%) 
Spinal compression fracture     
# participants affected / at risk   14/21893 (0.06%)   11/21802 (0.05%) 
Wrist fracture     
# participants affected / at risk   15/21893 (0.07%)   10/21802 (0.05%) 
Pelvic fracture     
# participants affected / at risk   9/21893 (0.04%)   11/21802 (0.05%) 
Subdural haematoma     
# participants affected / at risk   5/21893 (0.02%)   15/21802 (0.07%) 
Lumbar vertebral fracture     
# participants affected / at risk   9/21893 (0.04%)   10/21802 (0.05%) 
Road traffic accident     
# participants affected / at risk   9/21893 (0.04%)   9/21802 (0.04%) 
Facial bones fracture     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Head injury     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Joint dislocation     
# participants affected / at risk   5/21893 (0.02%)   11/21802 (0.05%) 
Spinal fracture     
# participants affected / at risk   6/21893 (0.03%)   9/21802 (0.04%) 
Laceration     
# participants affected / at risk   8/21893 (0.04%)   6/21802 (0.03%) 
Lower limb fracture     
# participants affected / at risk   8/21893 (0.04%)   6/21802 (0.03%) 
Fall     
# participants affected / at risk   4/21893 (0.02%)   9/21802 (0.04%) 
Tendon rupture     
# participants affected / at risk   10/21893 (0.05%)   3/21802 (0.01%) 
Fibula fracture     
# participants affected / at risk   7/21893 (0.03%)   4/21802 (0.02%) 
Tibia fracture     
# participants affected / at risk   3/21893 (0.01%)   8/21802 (0.04%) 
Traumatic brain injury     
# participants affected / at risk   5/21893 (0.02%)   5/21802 (0.02%) 
Cervical vertebral fracture     
# participants affected / at risk   5/21893 (0.02%)   4/21802 (0.02%) 
Hand fracture     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Meniscus lesion     
# participants affected / at risk   1/21893 (0.00%)   8/21802 (0.04%) 
Foot fracture     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Forearm fracture     
# participants affected / at risk   7/21893 (0.03%)   1/21802 (0.00%) 
Brain contusion     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Multiple injuries     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Overdose     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Pubis fracture     
# participants affected / at risk   1/21893 (0.00%)   6/21802 (0.03%) 
Thoracic vertebral fracture     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Ulna fracture     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Injury     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Multiple fractures     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Post procedural haemorrhage     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Metabolism and nutrition disorders     
Dehydration     
# participants affected / at risk   24/21893 (0.11%)   25/21802 (0.11%) 
Diabetes mellitus inadequate control     
# participants affected / at risk   22/21893 (0.10%)   20/21802 (0.09%) 
Hypoglycaemia     
# participants affected / at risk   23/21893 (0.11%)   18/21802 (0.08%) 
Diabetes mellitus     
# participants affected / at risk   18/21893 (0.08%)   18/21802 (0.08%) 
Type 2 diabetes mellitus     
# participants affected / at risk   16/21893 (0.07%)   12/21802 (0.06%) 
Hyponatraemia     
# participants affected / at risk   9/21893 (0.04%)   11/21802 (0.05%) 
Hypokalaemia     
# participants affected / at risk   8/21893 (0.04%)   9/21802 (0.04%) 
Diabetic foot     
# participants affected / at risk   5/21893 (0.02%)   7/21802 (0.03%) 
Hyperkalaemia     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Hypercholesterolaemia     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Hyperglycaemia     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Cachexia     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Electrolyte imbalance     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Gout     
# participants affected / at risk   6/21893 (0.03%)   0/21802 (0.00%) 
Hypomagnesaemia     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Musculoskeletal and connective tissue disorders     
Osteoarthritis     
# participants affected / at risk   87/21893 (0.40%)   108/21802 (0.50%) 
Intervertebral disc protrusion     
# participants affected / at risk   18/21893 (0.08%)   26/21802 (0.12%) 
Back pain     
# participants affected / at risk   15/21893 (0.07%)   20/21802 (0.09%) 
Spinal column stenosis     
# participants affected / at risk   19/21893 (0.09%)   14/21802 (0.06%) 
Rotator cuff syndrome     
# participants affected / at risk   8/21893 (0.04%)   12/21802 (0.06%) 
Arthralgia     
# participants affected / at risk   6/21893 (0.03%)   12/21802 (0.06%) 
Polymyalgia rheumatica     
# participants affected / at risk   12/21893 (0.05%)   5/21802 (0.02%) 
Intervertebral disc degeneration     
# participants affected / at risk   6/21893 (0.03%)   10/21802 (0.05%) 
Lumbar spinal stenosis     
# participants affected / at risk   7/21893 (0.03%)   9/21802 (0.04%) 
Rheumatoid arthritis     
# participants affected / at risk   8/21893 (0.04%)   8/21802 (0.04%) 
Spinal osteoarthritis     
# participants affected / at risk   8/21893 (0.04%)   8/21802 (0.04%) 
Arthritis     
# participants affected / at risk   5/21893 (0.02%)   4/21802 (0.02%) 
Bone pain     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Osteonecrosis     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Foot deformity     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Intervertebral disc disorder     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Musculoskeletal pain     
# participants affected / at risk   6/21893 (0.03%)   0/21802 (0.00%) 
Pain in extremity     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Spondylolisthesis     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Prostate cancer     
# participants affected / at risk   57/21893 (0.26%)   60/21802 (0.28%) 
Breast cancer     
# participants affected / at risk   48/21893 (0.22%)   46/21802 (0.21%) 
Colon cancer     
# participants affected / at risk   44/21893 (0.20%)   35/21802 (0.16%) 
Lung neoplasm malignant     
# participants affected / at risk   24/21893 (0.11%)   38/21802 (0.17%) 
Bladder cancer     
# participants affected / at risk   20/21893 (0.09%)   19/21802 (0.09%) 
Basal cell carcinoma     
# participants affected / at risk   12/21893 (0.05%)   21/21802 (0.10%) 
Gastric cancer     
# participants affected / at risk   15/21893 (0.07%)   13/21802 (0.06%) 
Pancreatic carcinoma     
# participants affected / at risk   15/21893 (0.07%)   12/21802 (0.06%) 
Rectal cancer     
# participants affected / at risk   10/21893 (0.05%)   13/21802 (0.06%) 
Bladder neoplasm     
# participants affected / at risk   13/21893 (0.06%)   9/21802 (0.04%) 
Squamous cell carcinoma     
# participants affected / at risk   8/21893 (0.04%)   9/21802 (0.04%) 
Malignant melanoma     
# participants affected / at risk   9/21893 (0.04%)   7/21802 (0.03%) 
Renal cancer     
# participants affected / at risk   10/21893 (0.05%)   6/21802 (0.03%) 
Hepatic neoplasm malignant     
# participants affected / at risk   8/21893 (0.04%)   7/21802 (0.03%) 
Pancreatic carcinoma metastatic     
# participants affected / at risk   7/21893 (0.03%)   8/21802 (0.04%) 
Lung adenocarcinoma     
# participants affected / at risk   7/21893 (0.03%)   7/21802 (0.03%) 
Neoplasm malignant     
# participants affected / at risk   9/21893 (0.04%)   5/21802 (0.02%) 
Lymphoma     
# participants affected / at risk   9/21893 (0.04%)   4/21802 (0.02%) 
Thyroid cancer     
# participants affected / at risk   8/21893 (0.04%)   5/21802 (0.02%) 
Metastases to liver     
# participants affected / at risk   6/21893 (0.03%)   6/21802 (0.03%) 
Prostatic adenoma     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Colon cancer metastatic     
# participants affected / at risk   6/21893 (0.03%)   5/21802 (0.02%) 
Brain neoplasm     
# participants affected / at risk   5/21893 (0.02%)   5/21802 (0.02%) 
Lung neoplasm     
# participants affected / at risk   4/21893 (0.02%)   6/21802 (0.03%) 
Transitional cell carcinoma     
# participants affected / at risk   6/21893 (0.03%)   4/21802 (0.02%) 
Uterine cancer     
# participants affected / at risk   6/21893 (0.03%)   4/21802 (0.02%) 
Bronchial carcinoma     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Non-hodgkin’s lymphoma     
# participants affected / at risk   6/21893 (0.03%)   3/21802 (0.01%) 
Breast cancer metastatic     
# participants affected / at risk   4/21893 (0.02%)   4/21802 (0.02%) 
Chronic lymphocytic leukaemia     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Colon neoplasm     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Lung cancer metastatic     
# participants affected / at risk   4/21893 (0.02%)   4/21802 (0.02%) 
Oesophageal carcinoma     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Renal neoplasm     
# participants affected / at risk   6/21893 (0.03%)   2/21802 (0.01%) 
Acute myeloid leukaemia     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Adenocarcinoma     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Colon adenoma     
# participants affected / at risk   2/21893 (0.01%)   5/21802 (0.02%) 
Endometrial cancer     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Hepatic neoplasm     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Metastatic malignant melanoma     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Metastatic neoplasm     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Multiple myeloma     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Prostate cancer metastatic     
# participants affected / at risk   1/21893 (0.00%)   6/21802 (0.03%) 
Renal cancer metastatic     
# participants affected / at risk   1/21893 (0.00%)   6/21802 (0.03%) 
Breast cancer recurrent     
# participants affected / at risk   4/21893 (0.02%)   2/21802 (0.01%) 
Meningioma     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Metastases to lung     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Ovarian neoplasm     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Renal cell carcinoma     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Nervous system disorders     
Cerebrovascular accident     
# participants affected / at risk   196/21893 (0.90%)   180/21802 (0.83%) 
Transient ischaemic attack     
# participants affected / at risk   69/21893 (0.32%)   57/21802 (0.26%) 
Syncope     
# participants affected / at risk   54/21893 (0.25%)   43/21802 (0.20%) 
Cerebrovascular disorder     
# participants affected / at risk   24/21893 (0.11%)   21/21802 (0.10%) 
Ischaemic stroke     
# participants affected / at risk   17/21893 (0.08%)   28/21802 (0.13%) 
Cerebral infarction     
# participants affected / at risk   23/21893 (0.11%)   11/21802 (0.05%) 
Epilepsy     
# participants affected / at risk   14/21893 (0.06%)   11/21802 (0.05%) 
Carotid artery stenosis     
# participants affected / at risk   13/21893 (0.06%)   10/21802 (0.05%) 
Vascular dementia     
# participants affected / at risk   12/21893 (0.05%)   7/21802 (0.03%) 
Cerebral ischaemia     
# participants affected / at risk   9/21893 (0.04%)   9/21802 (0.04%) 
Cerebral haemorrhage     
# participants affected / at risk   9/21893 (0.04%)   4/21802 (0.02%) 
Dementia     
# participants affected / at risk   4/21893 (0.02%)   9/21802 (0.04%) 
Dementia alzheimer’s type     
# participants affected / at risk   9/21893 (0.04%)   4/21802 (0.02%) 
Dizziness     
# participants affected / at risk   5/21893 (0.02%)   8/21802 (0.04%) 
Parkinson’s disease     
# participants affected / at risk   8/21893 (0.04%)   5/21802 (0.02%) 
Presyncope     
# participants affected / at risk   9/21893 (0.04%)   4/21802 (0.02%) 
Grand mal convulsion     
# participants affected / at risk   4/21893 (0.02%)   8/21802 (0.04%) 
Sciatica     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Cerebral arteriosclerosis     
# participants affected / at risk   7/21893 (0.03%)   4/21802 (0.02%) 
Subarachnoid haemorrhage     
# participants affected / at risk   7/21893 (0.03%)   4/21802 (0.02%) 
Brain oedema     
# participants affected / at risk   3/21893 (0.01%)   7/21802 (0.03%) 
Haemorrhagic stroke     
# participants affected / at risk   5/21893 (0.02%)   4/21802 (0.02%) 
Vertebrobasilar insufficiency     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Convulsion     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Encephalopathy     
# participants affected / at risk   6/21893 (0.03%)   2/21802 (0.01%) 
Parkinsonism     
# participants affected / at risk   6/21893 (0.03%)   1/21802 (0.00%) 
Brain stem infarction     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Embolic stroke     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Vascular encephalopathy     
# participants affected / at risk   2/21893 (0.01%)   4/21802 (0.02%) 
Psychiatric disorders     
Depression     
# participants affected / at risk   24/21893 (0.11%)   20/21802 (0.09%) 
Completed suicide     
# participants affected / at risk   5/21893 (0.02%)   7/21802 (0.03%) 
Delirium     
# participants affected / at risk   6/21893 (0.03%)   4/21802 (0.02%) 
Confusional state     
# participants affected / at risk   4/21893 (0.02%)   4/21802 (0.02%) 
Renal and urinary disorders     
Renal failure acute     
# participants affected / at risk   60/21893 (0.27%)   45/21802 (0.21%) 
Renal failure chronic     
# participants affected / at risk   27/21893 (0.12%)   30/21802 (0.14%) 
Renal failure     
# participants affected / at risk   26/21893 (0.12%)   27/21802 (0.12%) 
Nephrolithiasis     
# participants affected / at risk   14/21893 (0.06%)   20/21802 (0.09%) 
Urinary retention     
# participants affected / at risk   13/21893 (0.06%)   15/21802 (0.07%) 
Haematuria     
# participants affected / at risk   8/21893 (0.04%)   8/21802 (0.04%) 
Calculus ureteric     
# participants affected / at risk   10/21893 (0.05%)   4/21802 (0.02%) 
Urethral stenosis     
# participants affected / at risk   3/21893 (0.01%)   10/21802 (0.05%) 
Calculus bladder     
# participants affected / at risk   6/21893 (0.03%)   5/21802 (0.02%) 
Hydronephrosis     
# participants affected / at risk   8/21893 (0.04%)   3/21802 (0.01%) 
Urinary bladder polyp     
# participants affected / at risk   3/21893 (0.01%)   6/21802 (0.03%) 
Calculus urinary     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Cystitis haemorrhagic     
# participants affected / at risk   5/21893 (0.02%)   3/21802 (0.01%) 
Bladder neck obstruction     
# participants affected / at risk   1/21893 (0.00%)   5/21802 (0.02%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia     
# participants affected / at risk   27/21893 (0.12%)   31/21802 (0.14%) 
Uterine prolapse     
# participants affected / at risk   7/21893 (0.03%)   3/21802 (0.01%) 
Ovarian cyst     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Prostatitis     
# participants affected / at risk   3/21893 (0.01%)   4/21802 (0.02%) 
Uterine polyp     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease     
# participants affected / at risk   141/21893 (0.64%)   128/21802 (0.59%) 
Pulmonary embolism     
# participants affected / at risk   47/21893 (0.21%)   61/21802 (0.28%) 
Bronchitis     
# participants affected / at risk   61/21893 (0.28%)   43/21802 (0.20%) 
Respiratory failure     
# participants affected / at risk   32/21893 (0.15%)   37/21802 (0.17%) 
Asthma     
# participants affected / at risk   33/21893 (0.15%)   17/21802 (0.08%) 
Pulmonary oedema     
# participants affected / at risk   19/21893 (0.09%)   24/21802 (0.11%) 
Acute respiratory failure     
# participants affected / at risk   22/21893 (0.10%)   15/21802 (0.07%) 
Pleural effusion     
# participants affected / at risk   15/21893 (0.07%)   19/21802 (0.09%) 
Bronchitis chronic     
# participants affected / at risk   14/21893 (0.06%)   14/21802 (0.06%) 
Pneumonia aspiration     
# participants affected / at risk   10/21893 (0.05%)   14/21802 (0.06%) 
Dyspnoea     
# participants affected / at risk   13/21893 (0.06%)   10/21802 (0.05%) 
Epistaxis     
# participants affected / at risk   13/21893 (0.06%)   9/21802 (0.04%) 
Pneumothorax     
# participants affected / at risk   7/21893 (0.03%)   4/21802 (0.02%) 
Acute pulmonary oedema     
# participants affected / at risk   2/21893 (0.01%)   8/21802 (0.04%) 
Emphysema     
# participants affected / at risk   2/21893 (0.01%)   7/21802 (0.03%) 
Pleurisy     
# participants affected / at risk   6/21893 (0.03%)   3/21802 (0.01%) 
Pulmonary fibrosis     
# participants affected / at risk   2/21893 (0.01%)   6/21802 (0.03%) 
Sleep apnoea syndrome     
# participants affected / at risk   3/21893 (0.01%)   5/21802 (0.02%) 
Pulmonary hypertension     
# participants affected / at risk   4/21893 (0.02%)   3/21802 (0.01%) 
Bronchiectasis     
# participants affected / at risk   5/21893 (0.02%)   1/21802 (0.00%) 
Interstitial lung disease     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Respiratory arrest     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
Skin and subcutaneous tissue disorders     
Decubitus ulcer     
# participants affected / at risk   6/21893 (0.03%)   7/21802 (0.03%) 
Skin ulcer     
# participants affected / at risk   5/21893 (0.02%)   6/21802 (0.03%) 
Angioedema     
# participants affected / at risk   4/21893 (0.02%)   5/21802 (0.02%) 
Vascular disorders     
Hypertension     
# participants affected / at risk   82/21893 (0.37%)   83/21802 (0.38%) 
Arteriosclerosis     
# participants affected / at risk   22/21893 (0.10%)   30/21802 (0.14%) 
Hypertensive crisis     
# participants affected / at risk   26/21893 (0.12%)   21/21802 (0.10%) 
Circulatory collapse     
# participants affected / at risk   23/21893 (0.11%)   18/21802 (0.08%) 
Deep vein thrombosis     
# participants affected / at risk   13/21893 (0.06%)   24/21802 (0.11%) 
Peripheral arterial occlusive disease     
# participants affected / at risk   19/21893 (0.09%)   13/21802 (0.06%) 
Aortic aneurysm     
# participants affected / at risk   13/21893 (0.06%)   15/21802 (0.07%) 
Hypotension     
# participants affected / at risk   14/21893 (0.06%)   13/21802 (0.06%) 
Haematoma     
# participants affected / at risk   15/21893 (0.07%)   8/21802 (0.04%) 
Peripheral vascular disorder     
# participants affected / at risk   11/21893 (0.05%)   11/21802 (0.05%) 
Aortic stenosis     
# participants affected / at risk   11/21893 (0.05%)   7/21802 (0.03%) 
Venous thrombosis     
# participants affected / at risk   9/21893 (0.04%)   8/21802 (0.04%) 
Thrombophlebitis     
# participants affected / at risk   7/21893 (0.03%)   5/21802 (0.02%) 
Thrombosis     
# participants affected / at risk   4/21893 (0.02%)   8/21802 (0.04%) 
Orthostatic hypotension     
# participants affected / at risk   5/21893 (0.02%)   6/21802 (0.03%) 
Arterial occlusive disease     
# participants affected / at risk   4/21893 (0.02%)   6/21802 (0.03%) 
Intermittent claudication     
# participants affected / at risk   4/21893 (0.02%)   6/21802 (0.03%) 
Peripheral ischaemia     
# participants affected / at risk   5/21893 (0.02%)   4/21802 (0.02%) 
Arterial thrombosis limb     
# participants affected / at risk   4/21893 (0.02%)   4/21802 (0.02%) 
Hypovolaemic shock     
# participants affected / at risk   5/21893 (0.02%)   2/21802 (0.01%) 
Varicose vein     
# participants affected / at risk   6/21893 (0.03%)   1/21802 (0.00%) 
Venous thrombosis limb     
# participants affected / at risk   3/21893 (0.01%)   3/21802 (0.01%) 
* Events were collected by non-systematic assessment




  Other Adverse Events


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