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Study to Assess the Efficacy and Safety of PT010 Relative to PT003 and PT009 in Subjects With Moderate to Very Severe COPD (Ethos)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02465567
Recruitment Status : Completed
First Posted : June 8, 2015
Results First Posted : February 2, 2021
Last Update Posted : February 2, 2021
Sponsor:
Information provided by (Responsible Party):
Pearl Therapeutics, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition COPD
Interventions Drug: BGF MDI 320/14.4/9.6 μg
Drug: GFF MDI 14.4/9.6 μg
Drug: BGF MDI 160/14.4/9.6 μg
Drug: BFF MDI 320/9.6 μg
Enrollment 8588
Recruitment Details This study was conducted in 26 countries between July 2015 and July 2019.
Pre-assignment Details Subjects who successfully complete the Screening Period will then be randomized in a 1:1:1:1 scheme to BGF MDI 320/14.4/9.6 μg BID, BGF MDI 160/14.4/9.6 μg BID, BFF MDI 320/9.6 μg BID, or GFF MDI 14.4/9.6 μg BID, respectively.
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Period Title: Overall Study
Started 2157 2137 2143 2151
Completed 1708 1713 1580 1643
Not Completed 449 424 563 508
Reason Not Completed
Adverse Event             118             113             147             138
Lack of Efficacy             103             102             171             135
Withdrawal by Subject             104             94             123             130
Physician Decision             23             33             38             28
Major Protocol Deviation             24             26             22             25
Lost to Follow-up             25             21             19             15
Protocol Specified Criteria             20             10             9             12
Administrative Reasons             12             9             11             5
Randomized but not treated             1             5             4             5
enrolled in >1 studies             18             11             19             15
missing PI Signature             1             0             0             0
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg Total
Hide Arm/Group Description Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg Total of all reporting groups
Overall Number of Baseline Participants 2137 2121 2120 2131 8509
Hide Baseline Analysis Population Description
mITT population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2137 participants 2121 participants 2120 participants 2131 participants 8509 participants
64.6  (7.6) 64.6  (7.6) 64.8  (7.6) 64.6  (7.6) 64.7  (7.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2137 participants 2121 participants 2120 participants 2131 participants 8509 participants
Female
877
  41.0%
823
  38.8%
876
  41.3%
852
  40.0%
3428
  40.3%
Male
1260
  59.0%
1298
  61.2%
1244
  58.7%
1279
  60.0%
5081
  59.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2137 participants 2121 participants 2120 participants 2131 participants 8509 participants
Hispanic or Latino
400
  18.7%
393
  18.5%
426
  20.1%
401
  18.8%
1620
  19.0%
Not Hispanic or Latino
1690
  79.1%
1680
  79.2%
1649
  77.8%
1683
  79.0%
6702
  78.8%
Unknown or Not Reported
47
   2.2%
48
   2.3%
45
   2.1%
47
   2.2%
187
   2.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2137 participants 2121 participants 2120 participants 2131 participants 8509 participants
American Indian or Alaska Native
33
   1.5%
40
   1.9%
30
   1.4%
39
   1.8%
142
   1.7%
Asian
162
   7.6%
166
   7.8%
157
   7.4%
166
   7.8%
651
   7.7%
Native Hawaiian or Other Pacific Islander
2
   0.1%
0
   0.0%
0
   0.0%
0
   0.0%
2
   0.0%
Black or African American
78
   3.6%
88
   4.1%
75
   3.5%
64
   3.0%
305
   3.6%
White
1819
  85.1%
1783
  84.1%
1808
  85.3%
1816
  85.2%
7226
  84.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
43
   2.0%
44
   2.1%
50
   2.4%
46
   2.2%
183
   2.2%
1.Primary Outcome
Title Adjusted Rate of Moderate or Severe Exacerbations
Hide Description Adjusted Rate of Moderate or Severe Exacerbations
Time Frame 52-week treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 2137 2121 2120 2131
Least Squares Mean (Standard Error)
Unit of Measure: Moderate or Severe Exacerbations
1.08  (0.04) 1.07  (0.04) 1.42  (0.05) 1.24  (0.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.69 to 0.83
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0027
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.79 to 0.95
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.69 to 0.83
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.79 to 0.95
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to First Moderate or Severe COPD Exacerbation
Hide Description Time to first moderate or severe COPD exacerbation (proportion with event reported as median time was not reached, statistical analyses are based upon time to event)
Time Frame 52 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 2137 2121 2120 2131
Measure Type: Count of Participants
Unit of Measure: Participants
1026
  48.0%
1013
  47.8%
1056
  49.8%
1085
  50.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0035
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.880
Confidence Interval (2-Sided) 95%
0.807 to 0.959
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.057
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.887
Confidence Interval (2-Sided) 95%
0.814 to 0.966
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.866
Confidence Interval (2-Sided) 95%
0.794 to 0.944
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.873
Confidence Interval (2-Sided) 95%
0.801 to 0.951
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks
Hide Description Change from baseline in average daily rescue Ventolin HFA use over 24 weeks
Time Frame 24 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 1425 1389 1387 1426
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Puffs
-1.2
(-1.3 to -1.1)
-1.0
(-1.2 to -0.9)
-0.7
(-0.8 to -0.5)
-0.8
(-0.9 to -0.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Linear Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.51
Confidence Interval (2-Sided) 95%
-0.68 to -0.34
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Linear Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.37
Confidence Interval (2-Sided) 95%
-0.54 to -0.20
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Linear Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.35
Confidence Interval (2-Sided) 95%
-0.53 to -0.18
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0127
Comments [Not Specified]
Method Linear Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.22
Confidence Interval (2-Sided) 95%
-0.39 to -0.05
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score
Hide Description Percentage of subjects achieving a minimal clinically important difference (MCID) of 4 units or more in SGRQ (St. George's Respiratory Questionnaire) total score at Week 24
Time Frame at Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 2119 2102 2096 2122
Measure Type: Count of Participants
Unit of Measure: Participants
1068
  50.4%
1024
  48.7%
893
  42.6%
949
  44.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.358
Confidence Interval (2-Sided) 95%
1.199 to 1.539
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.246
Confidence Interval (2-Sided) 95%
1.100 to 1.410
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0004
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.283
Confidence Interval (2-Sided) 95%
1.133 to 1.454
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0103
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.177
Confidence Interval (2-Sided) 95%
1.039 to 1.333
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time to Death (All Cause)
Hide Description Subject Deaths (all cause)
Time Frame 52 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 2137 2121 2120 2131
Measure Type: Count of Participants
Unit of Measure: Participants
28
   1.3%
39
   1.8%
49
   2.3%
34
   1.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0111
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.544
Confidence Interval (2-Sided) 95%
0.340 to 0.870
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3401
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.782
Confidence Interval (2-Sided) 95%
0.472 to 1.296
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2690
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.789
Confidence Interval (2-Sided) 95%
0.518 to 1.201
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5918
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.134
Confidence Interval (2-Sided) 95%
0.716 to 1.796
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Rate of Severe COPD Exacerbations
Hide Description Rate of severe COPD exacerbations
Time Frame 52 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
mITT Population
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description:
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg
Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg
Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
Overall Number of Participants Analyzed 2137 2121 2120 2131
Least Squares Mean (Standard Error)
Unit of Measure: Severe Exacerbations
0.13  (0.01) 0.14  (0.01) 0.15  (0.01) 0.16  (0.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6552
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.69 to 1.03
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BGF MDI 320/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0221
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.66 to 0.97
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, GFF MDI 14.4/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2157
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.72 to 1.08
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BGF MDI 160/14.4/9.6 μg, BFF MDI 320/9.6 μg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0647
Comments [Not Specified]
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.69 to 1.01
Estimation Comments [Not Specified]
Time Frame Serious Adverse events were collected from the time subject signed Informed Consent to the time of the final follow-up telephone call. Adverse Events were collected from the time subject was randomized
Adverse Event Reporting Description The Safety Population was defined as all subjects who were randomized to treatment and received at least 1 dose of the study drug
 
Arm/Group Title BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Hide Arm/Group Description Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
All-Cause Mortality
BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   27/2144 (1.26%)      42/2124 (1.98%)      47/2125 (2.21%)      35/2136 (1.64%)    
Hide Serious Adverse Events
BGF MDI 320/14.4/9.6 μg BGF MDI 160/14.4/9.6 μg GFF MDI 14.4/9.6 μg BFF MDI 320/9.6 μg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   426/2144 (19.87%)      445/2124 (20.95%)      433/2125 (20.38%)      440/2136 (20.60%)    
Blood and lymphatic system disorders         
Anaemia † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Iron deficiancy anaemia † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Anaemia macrocytic † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Immune thrombocytopenic purpura † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Lymphadenopathy † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Neutropenia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Thrombocytopenia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Cardiac disorders         
Acute myocardial infarction † 1  7/2144 (0.33%)  8 10/2124 (0.47%)  10 17/2125 (0.80%)  18 7/2136 (0.33%)  7
Atrial fibrilation † 1  9/2144 (0.42%)  9 8/2124 (0.38%)  8 14/2125 (0.66%)  15 3/2136 (0.14%)  3
Myocardial infarction † 1  5/2144 (0.23%)  5 5/2124 (0.24%)  5 7/2125 (0.33%)  7 4/2136 (0.19%)  4
Coronary artery disease † 1  5/2144 (0.23%)  5 5/2124 (0.24%)  5 7/2125 (0.33%)  7 1/2136 (0.05%)  1
Cardiac failure congestive † 1  5/2144 (0.23%)  6 3/2124 (0.14%)  3 5/2125 (0.24%)  6 2/2136 (0.09%)  2
Cardiac arrest † 1  3/2144 (0.14%)  3 1/2124 (0.05%)  1 8/2125 (0.38%)  8 0/2136 (0.00%)  0
Angina pectoris † 1  3/2144 (0.14%)  3 0/2124 (0.00%)  0 3/2125 (0.14%)  3 5/2136 (0.23%)  5
Cardiac failure † 1  1/2144 (0.05%)  1 3/2124 (0.14%)  3 2/2125 (0.09%)  2 3/2136 (0.14%)  3
Angina unstable † 1  3/2144 (0.14%)  3 1/2124 (0.05%)  1 3/2125 (0.14%)  3 1/2136 (0.05%)  1
Cardiac failure acute † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 4/2125 (0.19%)  4 1/2136 (0.05%)  1
Cardiorespiratory arrest † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 4/2125 (0.19%)  4 2/2136 (0.09%)  2
Acute coronary syndrome † 1  1/2144 (0.05%)  1 3/2124 (0.14%)  3 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Stress cardiomyopathy † 1  0/2144 (0.00%)  0 3/2124 (0.14%)  3 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Arteriosclerosis coronary artery † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 2/2136 (0.09%)  2
Atrial flutter † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Supraventricular tachycardia † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Arrhythmia † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Bradycardia † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Acute left ventricular failure † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Atrioventricular block complete † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Coronary artery occulsion † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Myocardial ischaemia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Pulseless electrical activity † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Ventricular fibrillation † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Atriventricular block second degree † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cardiac disorder † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cardio-respiratory distress † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cardiac failure chronic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cardiogenic shock † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cardiovascular disorder † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cardiovascular insufficency † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Coronary artery stenosis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Hypertensive heart disease † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Ischaemic cardiomyopathy † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Left ventricular failure † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Mitral valve incompetence † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Myocarditis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Right ventricular failure † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Sinus node dysfunction † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Tachycardia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Tricuspid valve incompetence † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Trifascicular black † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Ventricular tachycardia † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cor pulmonale † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Ear and labyrinth disorders         
Vertigo † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Endocrine disorders         
Adrenal mass † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Goitre † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Eye disorders         
Cataract † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Retinal detachment † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Eyelid ptosis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Retinal vascular thrombosis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Visual impairment † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Retinal degeneration † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastrointestinal disorders         
Gastrointestinal haemorrhage † 1  2/2144 (0.09%)  3 2/2124 (0.09%)  2 1/2125 (0.05%)  1 2/2136 (0.09%)  2
Small intestine obstruction † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 2/2125 (0.09%)  2 2/2136 (0.09%)  2
Abdonimal pain † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Inguinal hernia † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Colitis † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Pancreatitis acute † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Constipation † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Enteritis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Upper gastrointestinal haemorrhage † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Abdominal hernia † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Colitis ulcerative † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Diverticular perforation † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Duodenal ulcenrn † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Gastrooesophageal reflux disease † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Ileus † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Large intestine polyp † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Anal fissure † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Colitis microscopic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Diaphragmatic hernia † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Diverticulum † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Diverticulum intestinal haemorrhagic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Duodenal perforation † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Duodenal ulcer haemorrhage † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Dysphagia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Enterocolitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Gastric ulcer † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastric ulcer perforation † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastritis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Haemoroidal haemorrhage † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Haemorrhoids thrombosed † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Impaired gastric emptying † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Intestinal Infarction † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Intestinal obstruction † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Intestinal polyp † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Mesenteric artery stenosis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Obstructive pancreatitis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pharyngo-oesophageal diverticulum † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Retroperitoneal haemorrhage † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Toothache † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Varices oesophageal † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Vomiting † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Erosive oesophagitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Large intestinal haemorrhage † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
General disorders         
Death † 1  1/2144 (0.05%)  1 4/2124 (0.19%)  4 7/2125 (0.33%)  7 2/2136 (0.09%)  2
Chest pain † 1  3/2144 (0.14%)  3 4/2124 (0.19%)  4 2/2125 (0.09%)  2 2/2136 (0.09%)  2
Multiple organ dysfunction syndrome † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Sudden death † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Non-cardiac chest pain † 1  4/2144 (0.19%)  4 1/2124 (0.05%)  1 2/2125 (0.09%)  2 4/2136 (0.19%)  4
Drug withdrawal syndrome † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Oedema peripheral † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Asthenia † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Capsular contracture associated with breast implant † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Fatigue † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pain † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Soft tissue inflamation † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Sudden cardiac death † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Systemic inflammatory response syndrome † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hepatobiliary disorders         
Cholecystitis acute † 1  2/2144 (0.09%)  2 2/2124 (0.09%)  2 3/2125 (0.14%)  3 3/2136 (0.14%)  3
Cholelithiasis † 1  3/2144 (0.14%)  3 0/2124 (0.00%)  0 4/2125 (0.19%)  4 1/2136 (0.05%)  1
Cholecystitis † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Hepatic cirrohsis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Bile duct obstruction † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cholangitis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cholecystitis Chronic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Hepatic failure † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Hepatic function abnormal † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hepatitis toxic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Immune system disorders         
Drug hypersensitivity † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Anaphylactic reaction † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Allergy to arthropod sting † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Type I hypersensitivity † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Infections and infestations         
Pneumonia † 1  61/2144 (2.85%)  63 59/2124 (2.78%)  64 35/2125 (1.65%)  37 55/2136 (2.57%)  57
Sepsis † 1  7/2144 (0.33%)  8 5/2124 (0.24%)  5 5/2125 (0.24%)  5 3/2136 (0.14%)  3
Cellulitis † 1  4/2144 (0.19%)  4 6/2124 (0.28%)  6 4/2125 (0.19%)  4 3/2136 (0.14%)  3
Influenza † 1  4/2144 (0.19%)  4 2/2124 (0.09%)  2 2/2125 (0.09%)  2 7/2136 (0.33%)  7
Diverticulitis † 1  3/2144 (0.14%)  4 3/2124 (0.14%)  3 3/2125 (0.14%)  3 4/2136 (0.19%)  5
Bronchitis † 1  2/2144 (0.09%)  2 3/2124 (0.14%)  3 4/2125 (0.19%)  4 3/2136 (0.14%)  3
Urinary tract infection † 1  1/2144 (0.05%)  1 4/2124 (0.19%)  4 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Respiratory tract infection † 1  2/2144 (0.09%)  3 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Lung infection † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 1/2125 (0.05%)  1 2/2136 (0.09%)  2
Lower respiratory tract infection † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Appendicitis † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Septic shock † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Erysipelas † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Pneumonia bacterial † 1  3/2144 (0.14%)  3 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pneumonia viral † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Staphylococcal infection † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 3/2125 (0.14%)  3 0/2136 (0.00%)  0
Wound infection † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Anal abscess † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Device related infection † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastroenteritis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Peritonitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Pneumonia pneumococcal † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Pulmonary tuberculosis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Respiratory syncytial virus infection † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Urosepsis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Arthritis bacterial † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Bacterial pyelonephritis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Bronchitis viral † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Bronchopulmonary aspergillosis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Bronchopulmonary aspergillosis allergic † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Bursitis infective † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Campylobacter infection † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Catheter site cellulitits † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Cellulitis of male external genital organ † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cholecystitis infective † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Clostridium difficile colitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Colonic abscess † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Emphysematous cholecystitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Encephalitis brain stem † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Endocarditis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Epididymitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Gastroenteritis norovirus † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Gastroenteritis salmonella † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastroenteritis shigella † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Gastroenteritis viral † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
H1N1 influenza † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Histoplasmosis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Infected bite † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Infected dermal cyst † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Infective exacerbation of bronshiectasis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Laryngitis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Localised infection † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Mastitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Mastoiditis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Metapneumovirus infection † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Micrococcus infection † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Oesophageal candidiasis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Osteomyelitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Otosalpingitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Perichondritis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Periorbital cellulitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pneumonia pseudomonal † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Post procedural sepsis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pyelonephritis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Respiratory tract infection viral † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Sinusitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Soft tissue infection † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Tracheobronchitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Vaginal infection † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Viral infection † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pneumonia streptococcal † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Injury, poisoning and procedural complications         
Hip fracture † 1  4/2144 (0.19%)  4 3/2124 (0.14%)  3 1/2125 (0.05%)  1 5/2136 (0.23%)  5
Ankle fracture † 1  3/2144 (0.14%)  3 0/2124 (0.00%)  0 0/2125 (0.00%)  0 3/2136 (0.14%)  3
Fall † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Femoral neck fracture † 1  2/2144 (0.09%)  2 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Femur fracture † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Lower limb fracture † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Radius fracture † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Meniscus injury † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Road traffic accident † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Spinal compression fracture † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Abdominal wound dehiscene † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Foot fracture † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Lumbar vertebral fracture † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Multiple injuries † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Post procedural hemorrhage † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Thoracic vertebral fracture † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Tibia fracture † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Ulna fracture † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Accidental overdose † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Concussion † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Epicondylitis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Foreign body aspiration † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Foreign body in gastrointestinal tract † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Hand Fracture † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Humerous fracture † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Jaw fracture † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Joint dislocation † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Limb traumatic amputation † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Multiple fractures † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Ocular procedural complication † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pelvic fracture † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Procedural pneumothorax † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Pubis fracture † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Radiation proctitis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Sternal fracture † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Subdural hematoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Tendon rupture † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Upper limb fracture † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Venomous bite † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Wound decomposition † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Wound dehiscence † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Wrist fracture † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Rib fracture † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Contussion † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Penetrating abdominal trauma † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pneumoconiosis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Spinal fracture † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Thermal burn † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Toxicity to various agents † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Wound evisceration † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Investigations         
Troponin increased † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Blood folate decreased † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Blood magnesium decreased † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Electrocradiogram ST-T change † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Electrocardiogram abnormal † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Oxygen saturation decreased † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Prothrombin time abnormal † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Metabolism and nutrition disorders         
Fluid overload † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hyperglycaemia † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hypoglycaemia † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hyponatremia † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Abnormal loss of weight † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Dehydration † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Diabetes melitus † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Diabetes melitus inadequate control † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Hyperlipidemia † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Impaired fasting glucose † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Metabolic acidosis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Obesity † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Vitamin B12 deficiency † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Musculoskeletal and connective tissue disorders         
Osteorthritis † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 3/2125 (0.14%)  3 3/2136 (0.14%)  3
Back pain † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Intervertebral disc protrusion † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Osteonecrosis † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Rotator cuff syndrome † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 4/2125 (0.19%)  4 0/2136 (0.00%)  0
Lumbar spinal stenosis † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Arthralgia † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Flank pain † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Bursitis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Costochondritis † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Groin pain † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Intervertebral disc degeneration † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Muscular weakness † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Pain in extremity † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Rhabdomyolysis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Spinal ligament † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Spinal osteoarthritis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Spondylolisthesis † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Synovial cyst † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Synovitis † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cervical spinal stenosis † 1  1/2144 (0.05%)  1 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Musculoskeletal pain † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Lung neoplasm malignant † 1  4/2144 (0.19%)  4 5/2124 (0.24%)  5 2/2125 (0.09%)  2 4/2136 (0.19%)  4
Prostate cancer † 1  3/2144 (0.14%)  3 1/2124 (0.05%)  1 2/2125 (0.09%)  2 3/2136 (0.14%)  3
Lung adenocarcinoma † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 4/2125 (0.19%)  4 1/2136 (0.05%)  12
Non-small cell lung cancer † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Transitional cell carcinoma † 1  2/2144 (0.09%)  2 2/2124 (0.09%)  2 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Metastases to liver † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Oesophageal carcinoma † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Squamous cell carcinoma of lung † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Breast cancer † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Pancreatic carcinoma † 1  2/2144 (0.09%)  2 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Pancreatic carcinoma metastatic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 2/2125 (0.09%)  2 1/2136 (0.05%)  1
Small cell lung caner † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 2/2136 (0.09%)  2
Adenocarcinoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Basal cell carcinoma † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Benign lung neoplasm † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Bronchial carcinoma † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Colorectal cancer † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Malignant palate neoplasm † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Metastases to central nervous system † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Metastases to lung † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Oesophageal squamous cell carcinoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Squamous cell carcinoma † 1  0/2144 (0.00%)  0 2/2124 (0.09%)  2 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Abdominal wall neoplasm † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Acute myeloid leukaemia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Adenocarcinoma gastric † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Adenocarcinoma of colon † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Adenocarcinoma pancreas † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Adenosquamous cell lung cancer † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Bladder cancer † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Breast cancer in situ † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Breast cancer stage IV † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Colon cancer metastatic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Colon neopplasm † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Diffuse large B-cell lymphoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Gastric cancer † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Gastrointestinal lymphoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Gastrooesophageal cancer † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Glioblastoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Hepatic cancer metastatic † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Hepatocellular carcinoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Invasive breast carcinoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Invasive ductal breast carcinoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Laryngeal cancer † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Laryngeal squamous cell carcinoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Metasteses to bone † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Metastases to nervous system † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Metastatic bronchial carcinoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Oesophageal cancer metastatic † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Oropharyngeal squamous cell carcinoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Papillary renal cell carcinoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Rectal adenocarcinoma † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Recosigmoid cancer † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Renal cancer † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Renal cell carcinoma † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Renal neoplasm † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Tonsil cancer † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Non-Hodgkins lymphoma † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Rectal cancer † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Lung neoplasm † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Nervous system disorders         
Cerebrovascular accident † 1  8/2144 (0.37%)  8 2/2124 (0.09%)  3 4/2125 (0.19%)  4 3/2136 (0.14%)  3
Syncope † 1  2/2144 (0.09%)  2 3/2124 (0.14%)  3 1/2125 (0.05%)  1 4/2136 (0.19%)  4
Cerebral infarction † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 5/2136 (0.23%)  5
Carotid artery stenosis † 1  2/2144 (0.09%)  2 2/2124 (0.09%)  2 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Siezure † 1  1/2144 (0.05%)  1 4/2124 (0.19%)  4 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Encephalopathy † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 0/2125 (0.00%)  0 2/2136 (0.09%)  2
Cerebellar infarction † 1  1/2144 (0.05%)  1 1/2124 (0.05%)  1 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Dizziness † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Subarachnoid haemorrhage † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Ataxia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Cerebral ischaemia † 1  2/2144 (0.09%)  2 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Intracranial aneurysm † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 1/2136 (0.05%)  1
Ischaemic stroke † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 2/2125 (0.09%)  2 0/2136 (0.00%)  0
Aphasia † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Brain injury † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Carpal tunnel syndrome † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cerebral haemorrhage † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cerebrospinal fluid leakage † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Cervical radiculopathy † 1  0/2144 (0.00%)  0 1/2124 (0.05%)  1 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Colloid brain cyst † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Embolic Cerebral infarction † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0
Epilepsy † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 1/2125 (0.05%)  1 0/2136 (0.00%)  0
Guillain-Barre syndrome † 1  0/2144 (0.00%)  0 0/2124 (0.00%)  0 0/2125 (0.00%)  0 1/2136 (0.05%)  1
Haemorrhage intercranial † 1  1/2144 (0.05%)  1 0/2124 (0.00%)  0 0/2125 (0.00%)  0 0/2136 (0.00%)  0