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Comparing the Efficacy of Tiotropium + Olodaterol (5/5 µg) Fixed Dose Combination (FDC) Over Tiotropium 5µg in Reducing Moderate to Severe Exacerbations in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease.

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ClinicalTrials.gov Identifier: NCT02296138
Recruitment Status : Completed
First Posted : November 20, 2014
Results First Posted : June 4, 2018
Last Update Posted : June 4, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: olodaterol
Drug: tiotropium
Enrollment 7903
Recruitment Details A randomised, double-blind, active-controlled parallel group study to evaluate the effect of 52 weeks of once daily treatment of orally inhaled tiotropium + olodaterol fixed dose combination compared with tiotropium on Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with severe to very severe COPD.
Pre-assignment Details Following informed consent, the patient was entered into a maximum 7-day screening period to confirm the patient’s eligibility. At Visit 2, after a successful review of the inclusion and exclusion criteria, the patient was randomly allocated in equal ratio to receive once daily trial treatment and then entered the 360 days treatment phase.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Period Title: Overall Study
Started 3952 3951
Treated 3941 3939
Completed 3291 3451
Not Completed 661 500
Reason Not Completed
Adverse Event             348             259
Lack of Efficacy             59             37
Protocol Violation             35             36
Lost to Follow-up             9             12
Withdrawal by Subject             184             131
Not Treated             1             1
Patients with data irregularities             10             11
Other than specified             15             13
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg) Total
Hide Arm/Group Description Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days Total of all reporting groups
Overall Number of Baseline Participants 3941 3939 7880
Hide Baseline Analysis Population Description
Treated set (TS): This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Age, Continuous   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3941 participants 3939 participants 7880 participants
66.3  (8.5) 66.5  (8.4) 66.4  (8.5)
[1]
Measure Description: Age at the time of signing informed consent form is presented.
[2]
Measure Analysis Population Description: Treated Set
Sex: Female, Male   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3941 participants 3939 participants 7880 participants
Female
1100
  27.9%
1154
  29.3%
2254
  28.6%
Male
2841
  72.1%
2785
  70.7%
5626
  71.4%
[1]
Measure Description: Number of subjects is categorized as Male or Female.
[2]
Measure Analysis Population Description: Treated Set
Race (NIH/OMB)   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3941 participants 3939 participants 7880 participants
American Indian or Alaska Native
64
   1.6%
77
   2.0%
141
   1.8%
Asian
607
  15.4%
557
  14.1%
1164
  14.8%
Native Hawaiian or Other Pacific Islander
5
   0.1%
3
   0.1%
8
   0.1%
Black or African American
52
   1.3%
58
   1.5%
110
   1.4%
White
3113
  79.0%
3134
  79.6%
6247
  79.3%
More than one race
20
   0.5%
22
   0.6%
42
   0.5%
Unknown or Not Reported
80
   2.0%
88
   2.2%
168
   2.1%
[1]
Measure Description: Ethnicity was not captured in this trial
[2]
Measure Analysis Population Description: Treated Set
1.Primary Outcome
Title Annualised Rate of Moderate to Severe COPD Exacerbations During the Actual Treatment Period.
Hide Description Annualised rate of moderate to severe COPD exacerbations during the actual treatment period was calculated per treatment per patient−year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. Least Squares Means are actually exponentiated.
Time Frame From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description:
Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Overall Number of Participants Analyzed 3941 3939
Least Squares Mean (99% Confidence Interval)
Unit of Measure: Rate per patient−year
0.97
(0.90 to 1.03)
0.90
(0.84 to 0.96)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments Annualised rate of moderate to severe COPD exacerbation was analysed using a negative binomial model including the fixed, categorical effect of treatment as well as the logarithm of the treatment exposure as an offset.
Type of Statistical Test Superiority
Comments This hypothesis testing strategy ensures that the overall type I error is protected at 2-sided 0.01 level.
Statistical Test of Hypothesis P-Value 0.0498
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of rates vs. Tiotropium 5 μg
Estimated Value 0.93
Confidence Interval (2-Sided) 99%
0.85 to 1.02
Estimation Comments Ratio of events Tiotropium (5 μg) + Olodaterol (5 μg) versus Tiotropium (5 μg) is provided.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments Model was based on SPARK/FLAME- Covariates: Smoking status, baseline inhaled corticosteroid, Global Initiative on Chronic Obstructive Lung Disease stage, region, COPD Assessment Test score (replacing baseline symptom score), exacerbations treated with antibiotics/steroids history in previous year (replacing 1-year history of exacerbations)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0010
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of rates
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.84 to 0.96
Estimation Comments Ratio of rates Tiotropium (5 μg) versus Tiotropium (5 μg) + Olodaterol (5 μg) is provided.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments Model was based on HERMES- Covariates: age, sex, smoking status, baseline Long-acting Beta-agonist/inhaled corticosteroid, region and percent predicted post-bronchodilator Forced Expiratory Volume in One Second
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0080
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of rates
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.85 to 0.98
Estimation Comments Ratio of rates Tiotropium (5 μg) versus Tiotropium (5 μg) + Olodaterol (5 μg) is provided.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments Model was based on TRINITY/TRILOGY- Covariates: Treatment, region, severity of airflow limitation, and smoking status as effects, and exacerbations treated with antibiotics/steroids in previous year.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of rates
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.84 to 0.96
Estimation Comments Ratio of rates Tiotropium (5 μg) versus Tiotropium (5 μg) + Olodaterol (5 μg) is provided.
2.Secondary Outcome
Title Number of Patients With at Least One Moderate to Severe COPD Exacerbation During the Actual Treatment Period.
Hide Description Key secondary endpoint: Number of patients with at least one moderate to severe COPD exacerbation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation is presented.
Time Frame From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description:
Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Overall Number of Participants Analyzed 3941 3939
Measure Type: Number
Unit of Measure: Number of patients
1777 1746
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments A Cox’s proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-value
Type of Statistical Test Superiority
Comments This hypothesis testing strategy ensures that the overall type I error is protected at 2-sided 0.01 level.
Statistical Test of Hypothesis P-Value 0.1188
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 99%
0.87 to 1.03
Estimation Comments Tiotropium (5 μg) + Olodaterol (5 μg) versus Tiotropium (5 μg)
3.Secondary Outcome
Title Annualised Rate of Exacerbations Leading to Hospitalisation During the Actual Treatment Period.
Hide Description Annualised rate of exacerbations leading to hospitalisation during the actual treatment period was calculated per treatment per patient−year. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication.
Time Frame From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description:
Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Overall Number of Participants Analyzed 3941 3939
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Rate per patient−year
0.20
(0.18 to 0.22)
0.18
(0.16 to 0.20)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments Annualised rate of exacerbations leading to hospitalization was analysed using a negative binomial model including the fixed, categorical effect of treatment as well as the logarithm of the treatment exposure as an offset.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1265
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of events vs. Tiotropium 5 μg
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.76 to 1.03
Estimation Comments Ratio of events Tiotropium (5 μg) + Olodaterol (5 μg) versus Tiotropium (5 μg) is provided.
4.Secondary Outcome
Title Number of Patients With at Least One COPD Exacerbation Leading to Hospitalisation During the Actual Treatment Period.
Hide Description Number of patients with at least one COPD exacerbation leading to hospitalisation during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with at least one moderate to severe COPD exacerbation leading to hospitalisation is presented.
Time Frame From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description:
Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Overall Number of Participants Analyzed 3941 3939
Measure Type: Number
Unit of Measure: Number of patients
469 450
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments A Cox’s proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-value
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2773
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.82 to 1.06
Estimation Comments Tiotropium (5 μg) + Olodaterol (5 μg) versus Tiotropium (5 μg)
5.Secondary Outcome
Title Number of Patients With All-cause Mortality Occurring During the Actual Treatment Period.
Hide Description Number of patients with all-cause mortality occurring during the actual treatment period per treatment. The actual treatment period was defined as the interval from first in-take of study medication until 1 day after last in-take of study medication. The median was not estimated due to less than 50% of patients having an event. Hence the number of patients with all-cause mortality is presented.
Time Frame From first in-take of study medication until 1 day after last in-take of study medication, up to 361 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set (TS) -This patient set includes all randomised patients who were documented to have taken at least 1 dose of trial medication.
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description:
Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
Overall Number of Participants Analyzed 3941 3939
Measure Type: Number
Unit of Measure: Number of patients
32 36
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tiotropium 5 Microgram (μg), Tiotropium (5 μg) + Olodaterol (5 μg)
Comments A Cox’s proportional hazard model was used to estimate the hazard ratio and the corresponding Confidence Interval. A log-rank test was used to obtain the p-value
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7357
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.09
Confidence Interval (2-Sided) 95%
0.67 to 1.75
Estimation Comments Tiotropium (5 μg) + Olodaterol (5 μg) versus Tiotropium (5 μg)
Time Frame From the first dose of trial medication until 21 days after last in-take of trial medication, up to 381 days
Adverse Event Reporting Description Safety analyses were based on the treated set, which included all randomised patients who took at least 1 dose of trial medication during the randomised treatment period. Patients were only actively requested to report adverse events during the on-treatment period.
 
Arm/Group Title Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Hide Arm/Group Description Patient received 5 μg Tiotropium inhalation solution – RESPIMAT inhaler once daily orally for 360 days Patient received 5 μg Tiotropium + 5 μg Olodaterol fixed-dose combination (FDC) inhalation solution – RESPIMAT inhaler once daily orally for 360 days
All-Cause Mortality
Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Affected / at Risk (%) Affected / at Risk (%)
Total   98/3941 (2.49%)   92/3939 (2.34%) 
Show Serious Adverse Events Hide Serious Adverse Events
Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Affected / at Risk (%) Affected / at Risk (%)
Total   862/3941 (21.87%)   810/3939 (20.56%) 
Blood and lymphatic system disorders     
Anaemia  1  4/3941 (0.10%)  5/3939 (0.13%) 
Disseminated intravascular coagulation  1  1/3941 (0.03%)  0/3939 (0.00%) 
Iron deficiency anaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Lymphadenopathy  1  2/3941 (0.05%)  1/3939 (0.03%) 
Lymphadenopathy mediastinal  1  1/3941 (0.03%)  0/3939 (0.00%) 
Microcytic anaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pancytopenia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Cardiac disorders     
Accelerated idioventricular rhythm  1  0/3941 (0.00%)  1/3939 (0.03%) 
Acute coronary syndrome  1  4/3941 (0.10%)  1/3939 (0.03%) 
Acute left ventricular failure  1  1/3941 (0.03%)  1/3939 (0.03%) 
Acute myocardial infarction  1  9/3941 (0.23%)  11/3939 (0.28%) 
Angina pectoris  1  8/3941 (0.20%)  4/3939 (0.10%) 
Angina unstable  1  14/3941 (0.36%)  6/3939 (0.15%) 
Aortic valve disease mixed  1  0/3941 (0.00%)  1/3939 (0.03%) 
Aortic valve incompetence  1  1/3941 (0.03%)  0/3939 (0.00%) 
Aortic valve stenosis  1  2/3941 (0.05%)  1/3939 (0.03%) 
Arrhythmia  1  2/3941 (0.05%)  2/3939 (0.05%) 
Arteriosclerosis coronary artery  1  2/3941 (0.05%)  1/3939 (0.03%) 
Atrial fibrillation  1  12/3941 (0.30%)  18/3939 (0.46%) 
Atrial flutter  1  4/3941 (0.10%)  1/3939 (0.03%) 
Atrioventricular block second degree  1  1/3941 (0.03%)  0/3939 (0.00%) 
Bradycardia  1  2/3941 (0.05%)  0/3939 (0.00%) 
Cardiac arrest  1  8/3941 (0.20%)  8/3939 (0.20%) 
Cardiac failure  1  21/3941 (0.53%)  23/3939 (0.58%) 
Cardiac failure acute  1  2/3941 (0.05%)  1/3939 (0.03%) 
Cardiac failure chronic  1  5/3941 (0.13%)  5/3939 (0.13%) 
Cardiac failure congestive  1  14/3941 (0.36%)  17/3939 (0.43%) 
Cardio-respiratory arrest  1  6/3941 (0.15%)  3/3939 (0.08%) 
Cardiogenic shock  1  0/3941 (0.00%)  1/3939 (0.03%) 
Cardiomyopathy  1  1/3941 (0.03%)  1/3939 (0.03%) 
Cardiopulmonary failure  1  3/3941 (0.08%)  1/3939 (0.03%) 
Cardiovascular insufficiency  1  1/3941 (0.03%)  0/3939 (0.00%) 
Congestive cardiomyopathy  1  0/3941 (0.00%)  2/3939 (0.05%) 
Cor pulmonale  1  5/3941 (0.13%)  5/3939 (0.13%) 
Cor pulmonale acute  1  1/3941 (0.03%)  1/3939 (0.03%) 
Cor pulmonale chronic  1  3/3941 (0.08%)  0/3939 (0.00%) 
Coronary artery disease  1  11/3941 (0.28%)  8/3939 (0.20%) 
Coronary artery insufficiency  1  0/3941 (0.00%)  1/3939 (0.03%) 
Coronary artery occlusion  1  1/3941 (0.03%)  0/3939 (0.00%) 
Coronary artery stenosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Heart valve incompetence  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ischaemic cardiomyopathy  1  1/3941 (0.03%)  1/3939 (0.03%) 
Left ventricular dysfunction  1  0/3941 (0.00%)  1/3939 (0.03%) 
Left ventricular failure  1  1/3941 (0.03%)  1/3939 (0.03%) 
Microvascular coronary artery disease  1  1/3941 (0.03%)  0/3939 (0.00%) 
Mitral valve incompetence  1  1/3941 (0.03%)  1/3939 (0.03%) 
Mitral valve stenosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Myocardial haemorrhage  1  0/3941 (0.00%)  1/3939 (0.03%) 
Myocardial infarction  1  13/3941 (0.33%)  10/3939 (0.25%) 
Myocardial ischaemia  1  3/3941 (0.08%)  3/3939 (0.08%) 
Pericardial effusion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pericarditis  1  1/3941 (0.03%)  1/3939 (0.03%) 
Prinzmetal angina  1  1/3941 (0.03%)  1/3939 (0.03%) 
Right ventricular failure  1  2/3941 (0.05%)  3/3939 (0.08%) 
Sinoatrial block  1  1/3941 (0.03%)  0/3939 (0.00%) 
Sinus arrest  1  1/3941 (0.03%)  0/3939 (0.00%) 
Sinus tachycardia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Stress cardiomyopathy  1  2/3941 (0.05%)  1/3939 (0.03%) 
Supraventricular tachycardia  1  1/3941 (0.03%)  4/3939 (0.10%) 
Tachycardia  1  3/3941 (0.08%)  0/3939 (0.00%) 
Ventricular fibrillation  1  1/3941 (0.03%)  1/3939 (0.03%) 
Ventricular tachycardia  1  2/3941 (0.05%)  3/3939 (0.08%) 
Congenital, familial and genetic disorders     
Dermoid cyst  1  0/3941 (0.00%)  1/3939 (0.03%) 
Myocardial bridging  1  0/3941 (0.00%)  1/3939 (0.03%) 
Porokeratosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Retinal anomaly congenital  1  0/3941 (0.00%)  1/3939 (0.03%) 
Syringomyelia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Ear and labyrinth disorders     
Acute vestibular syndrome  1  1/3941 (0.03%)  0/3939 (0.00%) 
Deafness  1  1/3941 (0.03%)  1/3939 (0.03%) 
Deafness neurosensory  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hypoacusis  1  0/3941 (0.00%)  2/3939 (0.05%) 
Sudden hearing loss  1  2/3941 (0.05%)  0/3939 (0.00%) 
Vertigo  1  3/3941 (0.08%)  2/3939 (0.05%) 
Vertigo positional  1  0/3941 (0.00%)  1/3939 (0.03%) 
Eye disorders     
Age-related macular degeneration  1  1/3941 (0.03%)  0/3939 (0.00%) 
Amaurosis fugax  1  0/3941 (0.00%)  1/3939 (0.03%) 
Cataract  1  3/3941 (0.08%)  3/3939 (0.08%) 
Cataract subcapsular  1  1/3941 (0.03%)  0/3939 (0.00%) 
Eyelid ptosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Gaze palsy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Glaucoma  1  3/3941 (0.08%)  2/3939 (0.05%) 
Macular degeneration  1  0/3941 (0.00%)  2/3939 (0.05%) 
Macular fibrosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Macular hole  1  0/3941 (0.00%)  2/3939 (0.05%) 
Open angle glaucoma  1  2/3941 (0.05%)  0/3939 (0.00%) 
Retinal tear  1  0/3941 (0.00%)  1/3939 (0.03%) 
Retinal vein thrombosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Gastrointestinal disorders     
Abdominal hernia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Abdominal pain  1  2/3941 (0.05%)  4/3939 (0.10%) 
Abdominal pain lower  1  0/3941 (0.00%)  1/3939 (0.03%) 
Abdominal pain upper  1  0/3941 (0.00%)  1/3939 (0.03%) 
Chronic gastritis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Colitis  1  2/3941 (0.05%)  0/3939 (0.00%) 
Colitis ischaemic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Colitis ulcerative  1  1/3941 (0.03%)  1/3939 (0.03%) 
Constipation  1  1/3941 (0.03%)  3/3939 (0.08%) 
Diarrhoea  1  1/3941 (0.03%)  2/3939 (0.05%) 
Duodenal perforation  1  0/3941 (0.00%)  1/3939 (0.03%) 
Duodenal ulcer  1  0/3941 (0.00%)  2/3939 (0.05%) 
Dyspepsia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Dysphagia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Enteritis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Erosive oesophagitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Faecaloma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Food poisoning  1  1/3941 (0.03%)  0/3939 (0.00%) 
Gastric ulcer  1  0/3941 (0.00%)  3/3939 (0.08%) 
Gastric ulcer haemorrhage  1  0/3941 (0.00%)  1/3939 (0.03%) 
Gastritis  1  1/3941 (0.03%)  2/3939 (0.05%) 
Gastrointestinal haemorrhage  1  1/3941 (0.03%)  3/3939 (0.08%) 
Gastrointestinal necrosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Gastrooesophageal reflux disease  1  4/3941 (0.10%)  0/3939 (0.00%) 
Haematemesis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Haematochezia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Haemorrhoidal haemorrhage  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ileus  1  1/3941 (0.03%)  3/3939 (0.08%) 
Ileus paralytic  1  1/3941 (0.03%)  1/3939 (0.03%) 
Incarcerated inguinal hernia  1  2/3941 (0.05%)  0/3939 (0.00%) 
Incarcerated umbilical hernia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Inguinal hernia  1  3/3941 (0.08%)  4/3939 (0.10%) 
Intestinal obstruction  1  3/3941 (0.08%)  2/3939 (0.05%) 
Intestinal perforation  1  2/3941 (0.05%)  0/3939 (0.00%) 
Large intestine polyp  1  1/3941 (0.03%)  1/3939 (0.03%) 
Lower gastrointestinal haemorrhage  1  1/3941 (0.03%)  0/3939 (0.00%) 
Melaena  1  1/3941 (0.03%)  1/3939 (0.03%) 
Mesenteric artery thrombosis  1  1/3941 (0.03%)  1/3939 (0.03%) 
Nausea  1  1/3941 (0.03%)  0/3939 (0.00%) 
Necrotising colitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oesophageal obstruction  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oesophageal ulcer  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oesophagitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Oesophagitis ulcerative  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pancreatitis  1  1/3941 (0.03%)  3/3939 (0.08%) 
Pancreatitis acute  1  0/3941 (0.00%)  2/3939 (0.05%) 
Pancreatitis chronic  1  1/3941 (0.03%)  1/3939 (0.03%) 
Rectal haemorrhage  1  2/3941 (0.05%)  0/3939 (0.00%) 
Rectal polyp  1  0/3941 (0.00%)  1/3939 (0.03%) 
Small intestinal obstruction  1  1/3941 (0.03%)  2/3939 (0.05%) 
Subileus  1  1/3941 (0.03%)  0/3939 (0.00%) 
Umbilical hernia  1  3/3941 (0.08%)  1/3939 (0.03%) 
Upper gastrointestinal haemorrhage  1  0/3941 (0.00%)  2/3939 (0.05%) 
Volvulus  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vomiting  1  1/3941 (0.03%)  1/3939 (0.03%) 
General disorders     
Chest pain  1  11/3941 (0.28%)  10/3939 (0.25%) 
Death  1  14/3941 (0.36%)  3/3939 (0.08%) 
Hyperplasia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Impaired healing  1  1/3941 (0.03%)  0/3939 (0.00%) 
Incarcerated hernia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Malaise  1  2/3941 (0.05%)  0/3939 (0.00%) 
Medical device site haematoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Medical device site pain  1  0/3941 (0.00%)  1/3939 (0.03%) 
Multiple organ dysfunction syndrome  1  6/3941 (0.15%)  2/3939 (0.05%) 
Non-cardiac chest pain  1  0/3941 (0.00%)  3/3939 (0.08%) 
Oedema  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oedema peripheral  1  0/3941 (0.00%)  2/3939 (0.05%) 
Pain  1  0/3941 (0.00%)  2/3939 (0.05%) 
Peripheral swelling  1  2/3941 (0.05%)  1/3939 (0.03%) 
Pyrexia  1  1/3941 (0.03%)  4/3939 (0.10%) 
Sudden cardiac death  1  0/3941 (0.00%)  2/3939 (0.05%) 
Sudden death  1  1/3941 (0.03%)  1/3939 (0.03%) 
Systemic inflammatory response syndrome  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vascular stent restenosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Hepatobiliary disorders     
Acute hepatic failure  1  1/3941 (0.03%)  0/3939 (0.00%) 
Bile duct stone  1  2/3941 (0.05%)  2/3939 (0.05%) 
Cholangitis  1  1/3941 (0.03%)  2/3939 (0.05%) 
Cholangitis acute  1  0/3941 (0.00%)  1/3939 (0.03%) 
Cholecystitis  1  2/3941 (0.05%)  2/3939 (0.05%) 
Cholecystitis acute  1  4/3941 (0.10%)  0/3939 (0.00%) 
Cholecystitis chronic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cholelithiasis  1  2/3941 (0.05%)  4/3939 (0.10%) 
Drug-induced liver injury  1  1/3941 (0.03%)  2/3939 (0.05%) 
Hepatic cirrhosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hepatitis toxic  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hepatomegaly  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hyperbilirubinaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Jaundice cholestatic  1  1/3941 (0.03%)  1/3939 (0.03%) 
Immune system disorders     
Anaphylactic reaction  1  0/3941 (0.00%)  1/3939 (0.03%) 
Anaphylactic shock  1  2/3941 (0.05%)  0/3939 (0.00%) 
Infections and infestations     
Abdominal infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Abscess limb  1  0/3941 (0.00%)  1/3939 (0.03%) 
Acinetobacter infection  1  2/3941 (0.05%)  0/3939 (0.00%) 
Anal abscess  1  0/3941 (0.00%)  1/3939 (0.03%) 
Appendicitis  1  0/3941 (0.00%)  3/3939 (0.08%) 
Arthritis bacterial  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bacterial sepsis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Botulism  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bronchitis  1  7/3941 (0.18%)  4/3939 (0.10%) 
Bronchitis bacterial  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cellulitis  1  1/3941 (0.03%)  3/3939 (0.08%) 
Chronic sinusitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Chronic tonsillitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Clostridium difficile colitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Clostridium difficile infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Colon gangrene  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cystitis  1  0/3941 (0.00%)  2/3939 (0.05%) 
Diverticulitis  1  3/3941 (0.08%)  0/3939 (0.00%) 
Empyema  1  0/3941 (0.00%)  1/3939 (0.03%) 
Encephalitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Endocarditis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Epididymitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Erysipelas  1  0/3941 (0.00%)  2/3939 (0.05%) 
Gastroenteritis  1  4/3941 (0.10%)  4/3939 (0.10%) 
Gastroenteritis viral  1  1/3941 (0.03%)  0/3939 (0.00%) 
Gastrointestinal infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Giardiasis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Haemophilus infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Herpes zoster  1  1/3941 (0.03%)  4/3939 (0.10%) 
Infected skin ulcer  1  1/3941 (0.03%)  1/3939 (0.03%) 
Infectious colitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Infectious pleural effusion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Infective exacerbation of bronchiectasis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Infective exacerbation of chronic obstructive airways disease  1  15/3941 (0.38%)  15/3939 (0.38%) 
Infective glossitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Influenza  1  10/3941 (0.25%)  1/3939 (0.03%) 
Intestinal gangrene  1  1/3941 (0.03%)  0/3939 (0.00%) 
Lower respiratory tract infection  1  2/3941 (0.05%)  1/3939 (0.03%) 
Lower respiratory tract infection bacterial  1  1/3941 (0.03%)  0/3939 (0.00%) 
Lung abscess  1  3/3941 (0.08%)  1/3939 (0.03%) 
Lung infection  1  1/3941 (0.03%)  2/3939 (0.05%) 
Nasopharyngitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Neurosyphilis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Neutropenic sepsis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ophthalmic herpes zoster  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oral bacterial infection  1  1/3941 (0.03%)  0/3939 (0.00%) 
Peritonitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pharyngotonsillitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pneumonia  1  144/3941 (3.65%)  132/3939 (3.35%) 
Pneumonia bacterial  1  3/3941 (0.08%)  3/3939 (0.08%) 
Pneumonia pneumococcal  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pneumonia staphylococcal  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pneumonia streptococcal  1  0/3941 (0.00%)  1/3939 (0.03%) 
Post procedural infection  1  1/3941 (0.03%)  0/3939 (0.00%) 
Postoperative abscess  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pseudomonas infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Psoas abscess  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pulmonary sepsis  1  1/3941 (0.03%)  3/3939 (0.08%) 
Pulmonary tuberculosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pyelonephritis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pyelonephritis acute  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pyelonephritis chronic  1  0/3941 (0.00%)  1/3939 (0.03%) 
Respiratory tract infection  1  3/3941 (0.08%)  5/3939 (0.13%) 
Respiratory tract infection viral  1  0/3941 (0.00%)  1/3939 (0.03%) 
Rotavirus infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Scrotal abscess  1  0/3941 (0.00%)  1/3939 (0.03%) 
Sepsis  1  10/3941 (0.25%)  9/3939 (0.23%) 
Sepsis syndrome  1  0/3941 (0.00%)  1/3939 (0.03%) 
Septic arthritis staphylococcal  1  1/3941 (0.03%)  0/3939 (0.00%) 
Septic shock  1  5/3941 (0.13%)  3/3939 (0.08%) 
Staphylococcal infection  1  1/3941 (0.03%)  0/3939 (0.00%) 
Staphylococcal sepsis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Strongyloidiasis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Tracheobronchitis  1  2/3941 (0.05%)  0/3939 (0.00%) 
Tuberculosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Upper respiratory tract infection  1  1/3941 (0.03%)  3/3939 (0.08%) 
Urinary tract infection  1  12/3941 (0.30%)  3/3939 (0.08%) 
Urosepsis  1  1/3941 (0.03%)  1/3939 (0.03%) 
Viral infection  1  1/3941 (0.03%)  0/3939 (0.00%) 
Viral upper respiratory tract infection  1  0/3941 (0.00%)  1/3939 (0.03%) 
Wound infection  1  1/3941 (0.03%)  0/3939 (0.00%) 
Injury, poisoning and procedural complications     
Alcohol poisoning  1  2/3941 (0.05%)  0/3939 (0.00%) 
Anastomotic stenosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ankle fracture  1  1/3941 (0.03%)  3/3939 (0.08%) 
Brain contusion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Brain herniation  1  0/3941 (0.00%)  1/3939 (0.03%) 
Burns second degree  1  1/3941 (0.03%)  1/3939 (0.03%) 
Comminuted fracture  1  2/3941 (0.05%)  0/3939 (0.00%) 
Craniocerebral injury  1  0/3941 (0.00%)  1/3939 (0.03%) 
Fall  1  12/3941 (0.30%)  10/3939 (0.25%) 
Femoral neck fracture  1  1/3941 (0.03%)  2/3939 (0.05%) 
Femur fracture  1  2/3941 (0.05%)  2/3939 (0.05%) 
Fibula fracture  1  1/3941 (0.03%)  0/3939 (0.00%) 
Foot fracture  1  1/3941 (0.03%)  1/3939 (0.03%) 
Head injury  1  1/3941 (0.03%)  0/3939 (0.00%) 
Hip fracture  1  1/3941 (0.03%)  3/3939 (0.08%) 
Humerus fracture  1  3/3941 (0.08%)  3/3939 (0.08%) 
Laceration  1  0/3941 (0.00%)  1/3939 (0.03%) 
Limb injury  1  1/3941 (0.03%)  0/3939 (0.00%) 
Lower limb fracture  1  1/3941 (0.03%)  2/3939 (0.05%) 
Multiple fractures  1  2/3941 (0.05%)  1/3939 (0.03%) 
Multiple injuries  1  1/3941 (0.03%)  0/3939 (0.00%) 
Muscle rupture  1  1/3941 (0.03%)  0/3939 (0.00%) 
Nail injury  1  1/3941 (0.03%)  0/3939 (0.00%) 
Occupational exposure to product  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pelvic fracture  1  0/3941 (0.00%)  2/3939 (0.05%) 
Peripheral arterial reocclusion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Petroleum distillate poisoning  1  0/3941 (0.00%)  1/3939 (0.03%) 
Post procedural complication  1  0/3941 (0.00%)  1/3939 (0.03%) 
Post procedural haemorrhage  1  1/3941 (0.03%)  1/3939 (0.03%) 
Postoperative hernia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Postoperative ileus  1  0/3941 (0.00%)  1/3939 (0.03%) 
Procedural pain  1  0/3941 (0.00%)  1/3939 (0.03%) 
Radius fracture  1  1/3941 (0.03%)  0/3939 (0.00%) 
Rib fracture  1  1/3941 (0.03%)  4/3939 (0.10%) 
Road traffic accident  1  2/3941 (0.05%)  0/3939 (0.00%) 
Skull fracture  1  0/3941 (0.00%)  1/3939 (0.03%) 
Spinal compression fracture  1  3/3941 (0.08%)  1/3939 (0.03%) 
Spinal fracture  1  1/3941 (0.03%)  2/3939 (0.05%) 
Sternal fracture  1  0/3941 (0.00%)  2/3939 (0.05%) 
Stress fracture  1  0/3941 (0.00%)  2/3939 (0.05%) 
Subarachnoid haemorrhage  1  1/3941 (0.03%)  0/3939 (0.00%) 
Subdural haematoma  1  0/3941 (0.00%)  4/3939 (0.10%) 
Subdural haemorrhage  1  1/3941 (0.03%)  1/3939 (0.03%) 
Suture rupture  1  1/3941 (0.03%)  0/3939 (0.00%) 
Tendon injury  1  0/3941 (0.00%)  1/3939 (0.03%) 
Tendon rupture  1  2/3941 (0.05%)  0/3939 (0.00%) 
Thoracic vertebral fracture  1  2/3941 (0.05%)  0/3939 (0.00%) 
Tibia fracture  1  2/3941 (0.05%)  1/3939 (0.03%) 
Traumatic intracranial haemorrhage  1  0/3941 (0.00%)  1/3939 (0.03%) 
Urethral injury  1  1/3941 (0.03%)  0/3939 (0.00%) 
Urinary retention postoperative  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vascular procedure complication  1  0/3941 (0.00%)  1/3939 (0.03%) 
Wrist fracture  1  0/3941 (0.00%)  1/3939 (0.03%) 
Investigations     
Blood creatine phosphokinase increased  1  1/3941 (0.03%)  0/3939 (0.00%) 
Blood lactic acid increased  1  1/3941 (0.03%)  0/3939 (0.00%) 
Blood pressure increased  1  1/3941 (0.03%)  1/3939 (0.03%) 
Breath sounds absent  1  0/3941 (0.00%)  1/3939 (0.03%) 
C-reactive protein increased  1  0/3941 (0.00%)  1/3939 (0.03%) 
Liver function test increased  1  0/3941 (0.00%)  1/3939 (0.03%) 
PCO2 increased  1  0/3941 (0.00%)  1/3939 (0.03%) 
Troponin increased  1  1/3941 (0.03%)  1/3939 (0.03%) 
Weight decreased  1  1/3941 (0.03%)  0/3939 (0.00%) 
Metabolism and nutrition disorders     
Cachexia  1  2/3941 (0.05%)  0/3939 (0.00%) 
Decreased appetite  1  0/3941 (0.00%)  1/3939 (0.03%) 
Dehydration  1  4/3941 (0.10%)  2/3939 (0.05%) 
Diabetes mellitus  1  1/3941 (0.03%)  3/3939 (0.08%) 
Diabetes mellitus inadequate control  1  1/3941 (0.03%)  1/3939 (0.03%) 
Diabetic ketoacidosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Electrolyte depletion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Electrolyte imbalance  1  0/3941 (0.00%)  2/3939 (0.05%) 
Gout  1  1/3941 (0.03%)  1/3939 (0.03%) 
Hyperglycaemia  1  1/3941 (0.03%)  1/3939 (0.03%) 
Hypoalbuminaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hypocalcaemia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Hypoglycaemia  1  2/3941 (0.05%)  1/3939 (0.03%) 
Hypokalaemia  1  1/3941 (0.03%)  1/3939 (0.03%) 
Hyponatraemia  1  1/3941 (0.03%)  3/3939 (0.08%) 
Lactic acidosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Metabolic acidosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Type 2 diabetes mellitus  1  0/3941 (0.00%)  1/3939 (0.03%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Back pain  1  2/3941 (0.05%)  0/3939 (0.00%) 
Cartilage hypertrophy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Chondrocalcinosis pyrophosphate  1  1/3941 (0.03%)  0/3939 (0.00%) 
Compartment syndrome  1  1/3941 (0.03%)  0/3939 (0.00%) 
Fistula  1  0/3941 (0.00%)  1/3939 (0.03%) 
Haemarthrosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Intervertebral disc degeneration  1  1/3941 (0.03%)  0/3939 (0.00%) 
Intervertebral disc protrusion  1  1/3941 (0.03%)  1/3939 (0.03%) 
Muscle tightness  1  1/3941 (0.03%)  0/3939 (0.00%) 
Muscular weakness  1  1/3941 (0.03%)  1/3939 (0.03%) 
Musculoskeletal chest pain  1  1/3941 (0.03%)  2/3939 (0.05%) 
Neck pain  1  0/3941 (0.00%)  2/3939 (0.05%) 
Osteoarthritis  1  3/3941 (0.08%)  6/3939 (0.15%) 
Osteochondrosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Osteonecrosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Osteoporosis  1  2/3941 (0.05%)  0/3939 (0.00%) 
Polymyalgia rheumatica  1  1/3941 (0.03%)  2/3939 (0.05%) 
Rhabdomyolysis  1  2/3941 (0.05%)  0/3939 (0.00%) 
Sarcopenia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Sjogren's syndrome  1  1/3941 (0.03%)  1/3939 (0.03%) 
Spinal column stenosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Spinal pain  1  1/3941 (0.03%)  0/3939 (0.00%) 
Tenosynovitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Adenocarcinoma gastric  1  1/3941 (0.03%)  0/3939 (0.00%) 
Adenocarcinoma of colon  1  1/3941 (0.03%)  0/3939 (0.00%) 
Adrenal neoplasm  1  1/3941 (0.03%)  0/3939 (0.00%) 
B-cell lymphoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Basal cell carcinoma  1  6/3941 (0.15%)  10/3939 (0.25%) 
Basosquamous carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Bladder cancer  1  5/3941 (0.13%)  2/3939 (0.05%) 
Bladder cancer recurrent  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bladder neoplasm  1  2/3941 (0.05%)  3/3939 (0.08%) 
Bone neoplasm  1  1/3941 (0.03%)  0/3939 (0.00%) 
Brain neoplasm  1  1/3941 (0.03%)  1/3939 (0.03%) 
Breast cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bronchial carcinoma  1  1/3941 (0.03%)  2/3939 (0.05%) 
Carcinoid tumour  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cerebellopontine angle tumour  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cervix carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cholangiocarcinoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Chronic myeloid leukaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Colon cancer  1  4/3941 (0.10%)  2/3939 (0.05%) 
Colon cancer metastatic  1  0/3941 (0.00%)  1/3939 (0.03%) 
Colon neoplasm  1  0/3941 (0.00%)  1/3939 (0.03%) 
Colorectal cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Diffuse large B-cell lymphoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ear neoplasm  1  0/3941 (0.00%)  1/3939 (0.03%) 
Gastric cancer  1  1/3941 (0.03%)  6/3939 (0.15%) 
Hepatic cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hypopharyngeal cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Invasive ductal breast carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Laryngeal squamous cell carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Leukaemia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Lung adenocarcinoma  1  4/3941 (0.10%)  2/3939 (0.05%) 
Lung cancer metastatic  1  0/3941 (0.00%)  2/3939 (0.05%) 
Lung infiltration malignant  1  0/3941 (0.00%)  1/3939 (0.03%) 
Lung neoplasm  1  4/3941 (0.10%)  2/3939 (0.05%) 
Lung neoplasm malignant  1  7/3941 (0.18%)  13/3939 (0.33%) 
Lymphocytic leukaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Malignant melanoma  1  2/3941 (0.05%)  1/3939 (0.03%) 
Malignant neoplasm of unknown primary site  1  0/3941 (0.00%)  1/3939 (0.03%) 
Meningioma  1  0/3941 (0.00%)  2/3939 (0.05%) 
Metastases to adrenals  1  0/3941 (0.00%)  1/3939 (0.03%) 
Metastases to bone  1  3/3941 (0.08%)  2/3939 (0.05%) 
Metastases to central nervous system  1  1/3941 (0.03%)  1/3939 (0.03%) 
Metastases to liver  1  0/3941 (0.00%)  1/3939 (0.03%) 
Metastases to lymph nodes  1  0/3941 (0.00%)  1/3939 (0.03%) 
Metastatic lymphoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Metastatic squamous cell carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Mucoepidermoid carcinoma of salivary gland  1  0/3941 (0.00%)  1/3939 (0.03%) 
Myelodysplastic syndrome  1  0/3941 (0.00%)  1/3939 (0.03%) 
Neoplasm prostate  1  0/3941 (0.00%)  1/3939 (0.03%) 
Neuroendocrine tumour  1  0/3941 (0.00%)  1/3939 (0.03%) 
Non-small cell lung cancer  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oesophageal carcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oesophageal neoplasm  1  1/3941 (0.03%)  0/3939 (0.00%) 
Oral haemangioma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pancreatic carcinoma  1  2/3941 (0.05%)  2/3939 (0.05%) 
Pancreatic carcinoma metastatic  1  0/3941 (0.00%)  1/3939 (0.03%) 
Papillary renal cell carcinoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Penis carcinoma metastatic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pharyngeal cancer  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pharyngeal cancer metastatic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Plasma cell myeloma  1  0/3941 (0.00%)  2/3939 (0.05%) 
Prostate cancer  1  8/3941 (0.20%)  8/3939 (0.20%) 
Prostate cancer recurrent  1  0/3941 (0.00%)  2/3939 (0.05%) 
Prostatic adenoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Rectal adenocarcinoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Rectal neoplasm  1  1/3941 (0.03%)  0/3939 (0.00%) 
Renal adenoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Renal cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Renal cell carcinoma  1  0/3941 (0.00%)  1/3939 (0.03%) 
Renal neoplasm  1  0/3941 (0.00%)  1/3939 (0.03%) 
Small cell lung cancer  1  3/3941 (0.08%)  1/3939 (0.03%) 
Small cell lung cancer metastatic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Squamous cell carcinoma of lung  1  3/3941 (0.08%)  5/3939 (0.13%) 
Squamous cell carcinoma of skin  1  3/3941 (0.08%)  2/3939 (0.05%) 
Thyroid cancer  1  0/3941 (0.00%)  1/3939 (0.03%) 
Tongue neoplasm malignant stage unspecified  1  0/3941 (0.00%)  1/3939 (0.03%) 
Tonsil cancer  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vocal cord neoplasm  1  0/3941 (0.00%)  1/3939 (0.03%) 
Nervous system disorders     
Acoustic neuritis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Alcohol induced persisting dementia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Amnesia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Anterior interosseous syndrome  1  1/3941 (0.03%)  0/3939 (0.00%) 
Aphasia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Brain injury  1  0/3941 (0.00%)  1/3939 (0.03%) 
Brain oedema  1  0/3941 (0.00%)  1/3939 (0.03%) 
Brain stem infarction  1  0/3941 (0.00%)  1/3939 (0.03%) 
Carotid artery occlusion  1  0/3941 (0.00%)  2/3939 (0.05%) 
Carotid artery stenosis  1  3/3941 (0.08%)  2/3939 (0.05%) 
Carpal tunnel syndrome  1  1/3941 (0.03%)  1/3939 (0.03%) 
Cerebral haemorrhage  1  1/3941 (0.03%)  0/3939 (0.00%) 
Cerebral infarction  1  3/3941 (0.08%)  2/3939 (0.05%) 
Cerebral ischaemia  1  2/3941 (0.05%)  1/3939 (0.03%) 
Cerebral thrombosis  1  0/3941 (0.00%)  2/3939 (0.05%) 
Cerebrovascular accident  1  7/3941 (0.18%)  8/3939 (0.20%) 
Cervical radiculopathy  1  1/3941 (0.03%)  0/3939 (0.00%) 
Coma  1  0/3941 (0.00%)  2/3939 (0.05%) 
Dementia  1  0/3941 (0.00%)  3/3939 (0.08%) 
Diabetic neuropathy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Dizziness  1  1/3941 (0.03%)  1/3939 (0.03%) 
Embolic cerebral infarction  1  1/3941 (0.03%)  0/3939 (0.00%) 
Encephalopathy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Epilepsy  1  2/3941 (0.05%)  2/3939 (0.05%) 
Facial neuralgia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Facial paresis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Generalised tonic-clonic seizure  1  1/3941 (0.03%)  0/3939 (0.00%) 
Guillain-Barre syndrome  1  1/3941 (0.03%)  0/3939 (0.00%) 
Haemorrhagic stroke  1  1/3941 (0.03%)  0/3939 (0.00%) 
Headache  1  3/3941 (0.08%)  0/3939 (0.00%) 
Hemianaesthesia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hemianopia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hemiparesis  1  2/3941 (0.05%)  3/3939 (0.08%) 
Hypoxic-ischaemic encephalopathy  1  2/3941 (0.05%)  0/3939 (0.00%) 
Intracranial aneurysm  1  1/3941 (0.03%)  1/3939 (0.03%) 
Ischaemic stroke  1  4/3941 (0.10%)  5/3939 (0.13%) 
Lacunar stroke  1  0/3941 (0.00%)  1/3939 (0.03%) 
Loss of consciousness  1  1/3941 (0.03%)  1/3939 (0.03%) 
Mononeuropathy  1  1/3941 (0.03%)  0/3939 (0.00%) 
Monoplegia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Myasthenia gravis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Myelopathy  1  1/3941 (0.03%)  0/3939 (0.00%) 
Nerve root compression  1  1/3941 (0.03%)  0/3939 (0.00%) 
Paraparesis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Presyncope  1  1/3941 (0.03%)  0/3939 (0.00%) 
Psychomotor hyperactivity  1  1/3941 (0.03%)  0/3939 (0.00%) 
Quadriparesis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Quadriplegia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Radiculopathy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Sciatica  1  0/3941 (0.00%)  1/3939 (0.03%) 
Seizure  1  2/3941 (0.05%)  2/3939 (0.05%) 
Syncope  1  3/3941 (0.08%)  5/3939 (0.13%) 
Transient global amnesia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Transient ischaemic attack  1  3/3941 (0.08%)  4/3939 (0.10%) 
Tremor  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vertebrobasilar insufficiency  1  0/3941 (0.00%)  1/3939 (0.03%) 
Vocal cord paralysis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Product Issues     
Device breakage  1  0/3941 (0.00%)  1/3939 (0.03%) 
Device lead damage  1  0/3941 (0.00%)  1/3939 (0.03%) 
Device malfunction  1  2/3941 (0.05%)  0/3939 (0.00%) 
Psychiatric disorders     
Alcohol abuse  1  1/3941 (0.03%)  0/3939 (0.00%) 
Alcoholism  1  0/3941 (0.00%)  1/3939 (0.03%) 
Anxiety  1  1/3941 (0.03%)  1/3939 (0.03%) 
Brief psychotic disorder with marked stressors  1  0/3941 (0.00%)  1/3939 (0.03%) 
Completed suicide  1  1/3941 (0.03%)  1/3939 (0.03%) 
Delirium  1  2/3941 (0.05%)  3/3939 (0.08%) 
Depression  1  2/3941 (0.05%)  3/3939 (0.08%) 
Disorientation  1  0/3941 (0.00%)  1/3939 (0.03%) 
Major depression  1  1/3941 (0.03%)  1/3939 (0.03%) 
Mental disorder  1  1/3941 (0.03%)  0/3939 (0.00%) 
Mental status changes  1  0/3941 (0.00%)  1/3939 (0.03%) 
Panic attack  1  1/3941 (0.03%)  0/3939 (0.00%) 
Schizophrenia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Renal and urinary disorders     
Acute kidney injury  1  7/3941 (0.18%)  15/3939 (0.38%) 
Acute prerenal failure  1  1/3941 (0.03%)  0/3939 (0.00%) 
Calculus urinary  1  1/3941 (0.03%)  0/3939 (0.00%) 
Chronic kidney disease  1  1/3941 (0.03%)  3/3939 (0.08%) 
Haematuria  1  0/3941 (0.00%)  1/3939 (0.03%) 
Hydronephrosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Nephrolithiasis  1  0/3941 (0.00%)  3/3939 (0.08%) 
Obstructive uropathy  1  1/3941 (0.03%)  0/3939 (0.00%) 
Renal colic  1  1/3941 (0.03%)  0/3939 (0.00%) 
Renal failure  1  3/3941 (0.08%)  1/3939 (0.03%) 
Renal infarct  1  0/3941 (0.00%)  1/3939 (0.03%) 
Renal salt-wasting syndrome  1  0/3941 (0.00%)  1/3939 (0.03%) 
Ureterolithiasis  1  3/3941 (0.08%)  1/3939 (0.03%) 
Urethral fistula  1  0/3941 (0.00%)  1/3939 (0.03%) 
Urinary retention  1  3/3941 (0.08%)  4/3939 (0.10%) 
Reproductive system and breast disorders     
Acquired hydrocele  1  0/3941 (0.00%)  1/3939 (0.03%) 
Benign prostatic hyperplasia  1  4/3941 (0.10%)  4/3939 (0.10%) 
Cervical polyp  1  1/3941 (0.03%)  0/3939 (0.00%) 
Endometrial hyperplasia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Ovarian cyst ruptured  1  1/3941 (0.03%)  0/3939 (0.00%) 
Prostatitis  1  1/3941 (0.03%)  1/3939 (0.03%) 
Uterine polyp  1  1/3941 (0.03%)  0/3939 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  2/3941 (0.05%)  1/3939 (0.03%) 
Acute respiratory distress syndrome  1  0/3941 (0.00%)  2/3939 (0.05%) 
Acute respiratory failure  1  24/3941 (0.61%)  21/3939 (0.53%) 
Alveolitis allergic  1  0/3941 (0.00%)  1/3939 (0.03%) 
Aspiration  1  0/3941 (0.00%)  1/3939 (0.03%) 
Asthma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Atelectasis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Bronchial haemorrhage  1  1/3941 (0.03%)  0/3939 (0.00%) 
Bronchial obstruction  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bronchial secretion retention  1  0/3941 (0.00%)  1/3939 (0.03%) 
Bronchiectasis  1  1/3941 (0.03%)  1/3939 (0.03%) 
Bronchospasm  1  2/3941 (0.05%)  1/3939 (0.03%) 
Chronic obstructive pulmonary disease  1  405/3941 (10.28%)  394/3939 (10.00%) 
Chronic respiratory failure  1  4/3941 (0.10%)  1/3939 (0.03%) 
Cough  1  2/3941 (0.05%)  0/3939 (0.00%) 
Dyspnoea  1  11/3941 (0.28%)  6/3939 (0.15%) 
Dyspnoea exertional  1  1/3941 (0.03%)  0/3939 (0.00%) 
Emphysema  1  2/3941 (0.05%)  2/3939 (0.05%) 
Epistaxis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Haemoptysis  1  2/3941 (0.05%)  2/3939 (0.05%) 
Haemothorax  1  1/3941 (0.03%)  0/3939 (0.00%) 
Hypercapnia  1  0/3941 (0.00%)  2/3939 (0.05%) 
Hypoxia  1  4/3941 (0.10%)  3/3939 (0.08%) 
Laryngeal oedema  1  3/3941 (0.08%)  1/3939 (0.03%) 
Lung consolidation  1  0/3941 (0.00%)  1/3939 (0.03%) 
Non-cardiogenic pulmonary oedema  1  1/3941 (0.03%)  0/3939 (0.00%) 
Organising pneumonia  1  2/3941 (0.05%)  0/3939 (0.00%) 
Pleural effusion  1  8/3941 (0.20%)  5/3939 (0.13%) 
Pleurisy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pleuritic pain  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pneumonia aspiration  1  4/3941 (0.10%)  3/3939 (0.08%) 
Pneumothorax  1  9/3941 (0.23%)  9/3939 (0.23%) 
Pneumothorax spontaneous  1  1/3941 (0.03%)  1/3939 (0.03%) 
Pulmonary arterial hypertension  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pulmonary artery thrombosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pulmonary congestion  1  2/3941 (0.05%)  0/3939 (0.00%) 
Pulmonary embolism  1  5/3941 (0.13%)  11/3939 (0.28%) 
Pulmonary fibrosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pulmonary hypertension  1  4/3941 (0.10%)  3/3939 (0.08%) 
Pulmonary infarction  1  1/3941 (0.03%)  0/3939 (0.00%) 
Pulmonary mass  1  3/3941 (0.08%)  4/3939 (0.10%) 
Pulmonary oedema  1  1/3941 (0.03%)  2/3939 (0.05%) 
Reflux laryngitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Respiratory acidosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Respiratory disorder  1  0/3941 (0.00%)  2/3939 (0.05%) 
Respiratory failure  1  43/3941 (1.09%)  33/3939 (0.84%) 
Status asthmaticus  1  1/3941 (0.03%)  0/3939 (0.00%) 
Vocal cord polyp  1  0/3941 (0.00%)  1/3939 (0.03%) 
Skin and subcutaneous tissue disorders     
Dermatitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Diabetic foot  1  1/3941 (0.03%)  0/3939 (0.00%) 
Drug eruption  1  1/3941 (0.03%)  1/3939 (0.03%) 
Pemphigoid  1  1/3941 (0.03%)  0/3939 (0.00%) 
Skin necrosis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Skin ulcer  1  1/3941 (0.03%)  1/3939 (0.03%) 
Swelling face  1  1/3941 (0.03%)  0/3939 (0.00%) 
Surgical and medical procedures     
Enterostomy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Gallbladder operation  1  1/3941 (0.03%)  0/3939 (0.00%) 
Implantable defibrillator insertion  1  0/3941 (0.00%)  1/3939 (0.03%) 
Lung transplant  1  0/3941 (0.00%)  1/3939 (0.03%) 
Pancreatic operation  1  0/3941 (0.00%)  1/3939 (0.03%) 
Transurethral prostatectomy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Vascular disorders     
Aortic aneurysm  1  3/3941 (0.08%)  2/3939 (0.05%) 
Aortic aneurysm rupture  1  1/3941 (0.03%)  0/3939 (0.00%) 
Aortic arteriosclerosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Aortic stenosis  1  0/3941 (0.00%)  3/3939 (0.08%) 
Aortic thrombosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Arterial disorder  1  1/3941 (0.03%)  0/3939 (0.00%) 
Arteriosclerosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Blood pressure inadequately controlled  1  1/3941 (0.03%)  0/3939 (0.00%) 
Brachiocephalic arteriosclerosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Circulatory collapse  1  3/3941 (0.08%)  3/3939 (0.08%) 
Deep vein thrombosis  1  8/3941 (0.20%)  1/3939 (0.03%) 
Embolism  1  0/3941 (0.00%)  1/3939 (0.03%) 
Haematoma  1  0/3941 (0.00%)  2/3939 (0.05%) 
Hypertension  1  5/3941 (0.13%)  3/3939 (0.08%) 
Hypertensive crisis  1  9/3941 (0.23%)  6/3939 (0.15%) 
Hypotension  1  2/3941 (0.05%)  3/3939 (0.08%) 
Hypovolaemic shock  1  1/3941 (0.03%)  0/3939 (0.00%) 
Intermittent claudication  1  1/3941 (0.03%)  0/3939 (0.00%) 
Ischaemia  1  1/3941 (0.03%)  0/3939 (0.00%) 
Macroangiopathy  1  0/3941 (0.00%)  1/3939 (0.03%) 
Microscopic polyangiitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Orthostatic hypotension  1  1/3941 (0.03%)  0/3939 (0.00%) 
Peripheral arterial occlusive disease  1  3/3941 (0.08%)  3/3939 (0.08%) 
Peripheral artery aneurysm  1  1/3941 (0.03%)  0/3939 (0.00%) 
Peripheral artery occlusion  1  1/3941 (0.03%)  2/3939 (0.05%) 
Peripheral artery thrombosis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Peripheral embolism  1  0/3941 (0.00%)  1/3939 (0.03%) 
Peripheral ischaemia  1  0/3941 (0.00%)  1/3939 (0.03%) 
Phlebitis  1  1/3941 (0.03%)  0/3939 (0.00%) 
Subclavian artery occlusion  1  1/3941 (0.03%)  1/3939 (0.03%) 
Subgaleal haematoma  1  1/3941 (0.03%)  0/3939 (0.00%) 
Thromboangiitis obliterans  1  1/3941 (0.03%)  0/3939 (0.00%) 
Thrombophlebitis  1  0/3941 (0.00%)  1/3939 (0.03%) 
Thrombosis  1  1/3941 (0.03%)  3/3939 (0.08%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tiotropium 5 Microgram (μg) Tiotropium (5 μg) + Olodaterol (5 μg)
Affected / at Risk (%) Affected / at Risk (%)
Total   1786/3941 (45.32%)   1770/3939 (44.94%) 
Infections and infestations     
Viral upper respiratory tract infection  1  293/3941 (7.43%)  281/3939 (7.13%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1504/3941 (38.16%)  1519/3939 (38.56%) 
Dyspnoea  1  232/3941 (5.89%)  203/3939 (5.15%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
One site was closed for cause due to data irregularities. The data from the 21 patients at this site were excluded from the patient sets used for analysis.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02296138     History of Changes
Other Study ID Numbers: 1237.19
2014-002275-28 ( EudraCT Number: EudraCT )
First Submitted: November 19, 2014
First Posted: November 20, 2014
Results First Submitted: March 7, 2018
Results First Posted: June 4, 2018
Last Update Posted: June 4, 2018