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Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events) (CANTOS)

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: NCT01327846
Recruitment Status : Completed
First Posted : April 4, 2011
Results First Posted : January 22, 2020
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Atherosclerosis
Interventions Drug: Canakinumab
Drug: Placebo
Drug: Standard of care
Enrollment 10066
Recruitment Details 10066 patients enrolled in the Core phase (4 randomized groups); 5 patients enrolled in the safety set were not included in efficacy set. 5777 patients continued in the Extension phase (539 entered only the washout period, 5238 entered the treatment period(s)). The Core phase completed as planned; “terminated” applies to the Extension phase.
Pre-assignment Details A total of 17482 patients were screened, and 10102 patients completed the screening phase. A total of 6430 patients did not complete the screening phase due to screen failure.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Period Title: Core Phase
Started 2263 2284 2170 3344
Completed 2235 2252 2144 3311
Not Completed 28 32 26 33
Reason Not Completed
Subject decision (vital status: missing)             1             2             2             1
Subject decision (vital stat: unkn)             0             0             3             3
Subject decision (vital stat: dead)             1             3             4             4
Subject decision (vital stat: alive)             23             24             13             20
Lost to Follow-up             3             3             4             5
Period Title: Extension Phase
Started 1267 1287 1279 1944
Stopped/Discontinued Study at Washout 127 97 137 178
Completed Treatment Period 41 45 49 60
Details Missing 0 1 1 0
Completed 168 143 187 238
Not Completed 1099 1144 1092 1706
Reason Not Completed
Study terminated by sponsor             1073             1124             1067             1660
Withdrawal by Subject             20             13             19             37
Lost to Follow-up             4             3             4             7
Technical Problems             2             4             2             2
Arm/Group Title Group I Group II Group III Group IV Total
Hide Arm/Group Description Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Total of all reporting groups
Overall Number of Baseline Participants 2263 2284 2170 3344 10061
Hide Baseline Analysis Population Description
Full analysis set (FAS) – All randomized patients except for those who were misrandomized or from sites with serious GCP violations. Baseline characteristics data are presented for patients enrolled in the Core phase of the study.
Age, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2263 participants 2284 participants 2170 participants 3344 participants 10061 participants
< 65 1424 1428 1350 2089 6291
>= 65 839 856 820 1255 3770
[1]
Measure Analysis Population Description: FAS
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2263 participants 2284 participants 2170 participants 3344 participants 10061 participants
Female 606 575 541 865 2587
Male 1657 1709 1629 2479 7474
[1]
Measure Analysis Population Description: FAS
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 2263 participants 2284 participants 2170 participants 3344 participants 10061 participants
Caucasian 1804 1808 1772 2652 8036
Black 84 67 61 106 318
Asian 265 278 232 388 1163
Native American 47 49 41 82 219
Pacific Islander 0 0 1 1 2
Unknown 3 3 1 3 10
Other 60 79 62 112 313
[1]
Measure Analysis Population Description: FAS
1.Primary Outcome
Title Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components
Hide Description Time to occurrence of CEC (Cardiovascular clinical events adjudication committee) confirmed MACE, which was a composite endpoint consisting of CEC confirmed CV death, CEC confirmed non-fatal MI,or CEC confirmed non-fatal stroke. Patients with the CEC adjudicated reason for death of "Unknown" were counted as CV (cardiovascular) death.
Time Frame From randomization, to end of treatment plus 30 days, up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): All randomized patients except for those who were misrandomized or from sites with serious GCP violations
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 2263 2284 2170 3344
Measure Type: Number
Unit of Measure: Participants
MACE 322 320 313 535
CV death 151 144 137 235
MI (fatal and non-fatal) 174 159 169 292
MI (non-fatal) 171 158 168 291
Stroke (fatal and non-fatal) 51 63 58 92
Stroke (non-fatal) 51 63 58 91
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments H11: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 300 mg dose group is greater than or equal to the hazard rate of the placebo group
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.0648
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.75 to 0.99
Estimation Comments MACE
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments H21: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 150 mg dose group is greater than or equal to the hazard rate of the placebo group
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.0241
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.74 to 0.98
Estimation Comments MACE
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments H31: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 50 mg dose group is greater than or equal to the hazard rate of the placebo group.
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.1895
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.80 to 1.07
Estimation Comments MACE
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.572
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.77 to 1.16
Estimation Comments CV death
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.296
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.73 to 1.10
Estimation Comments CV death
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.369
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.73 to 1.12
Estimation Comments CV death
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.067
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.69 to 1.01
Estimation Comments MI (fatal and non-fatal)
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.006
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.63 to 0.92
Estimation Comments MI (fatal and non-fatal)
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.542
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.78 to 1.14
Estimation Comments MI (fatal and non-fatal)
Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.68 to 1.00
Estimation Comments MI (non-fatal)
Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.62 to 0.92
Estimation Comments MI (non-fatal)
Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.78 to 1.14
Estimation Comments MI (non-fatal)
Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.190
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.56 to 1.12
Estimation Comments Stroke (fatal and non-fatal)
Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.912
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.71 to 1.35
Estimation Comments Stroke (fatal and non-fatal)
Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.871
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.74 to 1.43
Estimation Comments Stroke (fatal and non-fatal)
Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.57 to 1.13
Estimation Comments Stroke (nonfatal)
Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.72 to 1.37
Estimation Comments Stroke (nonfatal)
Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Other
Comments A HR < 1 favors Canakinumab
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.75 to 1.45
Estimation Comments Stroke (nonfatal)
2.Primary Outcome
Title Substudy 1 (Core Phase): Change From Baseline in Carotid Plaque Burden in the Bifurcation Region of the Index Carotid Artery
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
3.Primary Outcome
Title Substudy 2 (Core Phase): Change From Baseline of the Insulin Secretion Rate (ISR) Relative to Glucose 0-30 Min Defined as Φ30 = AUCISR 0-30 / AUCGluc 0-30 Averaged Across the Year 3, 4, 5 Visits
Hide Description [Not Specified]
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
4.Secondary Outcome
Title Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization
Hide Description

Occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina requiring unplanned revascularization.

MACE includes CV death, non-fatal MI and non-fatal stroke. CEC = Clinical Endpoints Committee

Time Frame From randomization, to end of treatment pus 30 days, up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 2263 2284 2170 3344
Measure Type: Number
Unit of Measure: Participants
MACE or unstable angina 348 352 344 601
Unstable angina 34 38 38 85
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.0648
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.72 to 0.94
Estimation Comments MACE or unstable angina
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.0241
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.73 to 0.95
Estimation Comments MACE or unstable angina
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.1895
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.79 to 1.03
Estimation Comments MACE or unstable angina
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.007
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.39 to 0.86
Estimation Comments unstable angina
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.022
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.44 to 0.94
Estimation Comments unstable angina
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.086
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.48 to 1.05
Estimation Comments unstable angina
5.Secondary Outcome
Title Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization
Hide Description Time to CEC confirmed new onset of type 2 diabetes among those with pre-diabetes at randomization (i.e. excluding those that are normoglycemic at baseline)
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 1132 1094 1089 1645
Measure Type: Number
Unit of Measure: Participants
169 171 161 246
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.8456
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.83 to 1.23
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.8456
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.87 to 1.29
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.6541
Comments 1-sided adjusted for multiplicity using weighted Dunnett test. [significance level 0.0245]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.80 to 1.20
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke
Hide Description Occurrence of the composite endpoint consisting of all-cause mortality, non-fatal IM, or non-fatal stroke
Time Frame From randomization, to end of treatment plus 30 days, up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 2263 2284 2170 3344
Measure Type: Number
Unit of Measure: Participants
403 395 394 661
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.028
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.77 to 0.99
Estimation Comments All-cause mortality or MI or Stroke
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.75 to 0.96
Estimation Comments All-cause mortality or MI or Stroke
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.377
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.83 to 1.07
Estimation Comments All-cause mortality or MI or Stroke
7.Secondary Outcome
Title Core Phase All-cause Mortality
Hide Description Number of participant deaths
Time Frame From randomization, to end of treatment plus 30 days, up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 2263 2284 2170 3344
Measure Type: Number
Unit of Measure: Participants
239 238 228 375
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group I, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.406
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.79 to 1.10
Estimation Comments All-cause mortality
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group II, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.329
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.78 to 1.09
Estimation Comments All-cause mortality
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group III, Group IV
Comments [Not Specified]
Type of Statistical Test Superiority
Comments A HR < 1 favors Canakinumab
Statistical Test of Hypothesis P-Value 0.597
Comments 2-sided unadjusted p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.81 to 1.13
Estimation Comments All-cause mortality
8.Secondary Outcome
Title Summary of Adverse Events (Core Phase)
Hide Description Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the double-blind Core phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment.
Time Frame From randomization, to end of treatment plus 30 days, up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set: All patients who received at least one dose of study treatment and had at least one post-baseline safety assessment
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 2263 2285 2170 3348
Measure Type: Number
Unit of Measure: Participants
Patients with at least one AE 1987 1970 1872 2915
AEs suspected to be related tostudy drug 355 350 267 474
Patients with at least one SAE 836 812 741 1204
Discontinued due to SAEs 135 130 117 198
Discontinued due to non-seriousAEs 40 34 26 47
AEs leading to study treatmentinterruption 268 270 228 399
9.Secondary Outcome
Title Summary of Adverse Events (Extension Phase)
Hide Description Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the Extension phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment.
Time Frame From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Extension Safety set: All patients who received at least one dose of study treatment during the Core Phase and who entered the Extension phase.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 1267 1287 1279 1944
Measure Type: Number
Unit of Measure: Participants
Patients with at least one AE 788 845 793 1250
AEs suspected to be related tostudy drug 40 34 43 65
Patients with at least one SAE 310 326 322 465
Discontinued due to SAEs 67 71 71 98
Discontinued due to non-seriousAEs 8 6 12 8
AEs leading to study treatmentinterruption 59 72 62 100
10.Secondary Outcome
Title Substudy 1 (Core Phase): Change From Baseline of the Total Vessel Wall Area at Month 3 in the Bifurcation Region of the Index Carotid Artery
Hide Description [Not Specified]
Time Frame 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Substudy 1 (Core Phase): Mean Total Vessel Wall Area Across the Left and Right Carotid Artery at Month 3 and Month 24
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
12.Secondary Outcome
Title Substudy 1 (Core Phase): Change From Baseline in Corresponding Total Vessel Wall Area in the Left and Right Carotid Arteries
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
13.Secondary Outcome
Title Substudy 1 (Core Phase): The Existence of a Baseline Total Vessel Wall Area by Treatment Interaction as Well as the Consistency of the Treatment Effect Across Subgroups
Hide Description [Not Specified]
Time Frame 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
14.Secondary Outcome
Title Substudy 2 (Core Phase): Change From Baseline in Insulin Sensitivity Index
Hide Description [Not Specified]
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
15.Secondary Outcome
Title Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under Curve (AUC) 0-120 Min of Glucose Concentration, Insulin Concentration, Pro-insulin Concentration, and Insulin Concentration/Glucose Concentration Ratio
Hide Description [Not Specified]
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
16.Secondary Outcome
Title Substudy 2 (Core Phase): Change From Baseline in Fasting Pro-Insulin Concentration/Insulin Concentration Ratio
Hide Description [Not Specified]
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
17.Secondary Outcome
Title Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under the Curve (AUC) 0-120 Min of C-peptide Concentration
Hide Description [Not Specified]
Time Frame From randomization up to approximately 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data from subjects were not collected as the substudy was terminated prior to data collection.
Arm/Group Title Group I Group II Group III Group IV
Hide Arm/Group Description:
Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy
Overall Number of Participants Analyzed 0 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Core phase: From randomization to end of treatment plus 30 days; up to approximately 6 years; Extension phase: From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years.
Adverse Event Reporting Description AEs/SAEs are any signs or symptoms that occur during the study treatment. Groups I to IV show AE/SAEs during the Core phase; Group V shows AE/SAEs during the Extension phase. During the Core phase, CV events being study endpoints were exempt from AE/SAE reporting; in contrast, during the Extension phase, all CV events were reported as AEs/SAEs.
 
Arm/Group Title Group I Group II Group III Group IV Group V
Hide Arm/Group Description Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy.
All-Cause Mortality
Group I Group II Group III Group IV Group V
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   239/2263 (10.56%)   240/2285 (10.50%)   228/2170 (10.51%)   378/3348 (11.29%)   211/5777 (3.65%) 
Hide Serious Adverse Events
Group I Group II Group III Group IV Group V
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   759/2263 (33.54%)   743/2285 (32.52%)   686/2170 (31.61%)   1099/3348 (32.83%)   1216/5777 (21.05%) 
Blood and lymphatic system disorders           
Abnormal clotting factor  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anaemia  1  15/2263 (0.66%)  10/2285 (0.44%)  4/2170 (0.18%)  14/3348 (0.42%)  10/5777 (0.17%) 
Bone marrow oedema  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Coagulopathy  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Disseminated intravascular coagulation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Febrile neutropenia  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Haemorrhagic anaemia  1  4/2263 (0.18%)  2/2285 (0.09%)  5/2170 (0.23%)  1/3348 (0.03%)  1/5777 (0.02%) 
Heparin-induced thrombocytopenia  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hilar lymphadenopathy  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Histiocytosis haematophagic  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hypochromic anaemia  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Immune thrombocytopenic purpura  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Iron deficiency anaemia  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  3/3348 (0.09%)  1/5777 (0.02%) 
Leukocytosis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Leukopenia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Lymphadenitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Lymphadenopathy  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Lymphadenopathy mediastinal  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Microcytic anaemia  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Monoclonal B-cell lymphocytosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Normochromic normocytic anaemia  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Normocytic anaemia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Pancytopenia  1  1/2263 (0.04%)  2/2285 (0.09%)  0/2170 (0.00%)  3/3348 (0.09%)  1/5777 (0.02%) 
Polycythaemia  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Splenic infarction  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Splenomegaly  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Thrombocytopenia  1  5/2263 (0.22%)  0/2285 (0.00%)  3/2170 (0.14%)  3/3348 (0.09%)  0/5777 (0.00%) 
Thrombocytopenic purpura  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Cardiac disorders           
Acute coronary syndrome  1  6/2263 (0.27%)  1/2285 (0.04%)  4/2170 (0.18%)  4/3348 (0.12%)  14/5777 (0.24%) 
Acute left ventricular failure  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Acute myocardial infarction  1  2/2263 (0.09%)  2/2285 (0.09%)  2/2170 (0.09%)  7/3348 (0.21%)  71/5777 (1.23%) 
Adams-Stokes syndrome  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Angina pectoris  1  42/2263 (1.86%)  41/2285 (1.79%)  37/2170 (1.71%)  76/3348 (2.27%)  66/5777 (1.14%) 
Angina unstable  1  39/2263 (1.72%)  34/2285 (1.49%)  37/2170 (1.71%)  63/3348 (1.88%)  56/5777 (0.97%) 
Aortic valve incompetence  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Aortic valve stenosis  1  3/2263 (0.13%)  2/2285 (0.09%)  2/2170 (0.09%)  3/3348 (0.09%)  2/5777 (0.03%) 
Arrhythmia  1  4/2263 (0.18%)  0/2285 (0.00%)  1/2170 (0.05%)  3/3348 (0.09%)  0/5777 (0.00%) 
Arrhythmia supraventricular  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Arteriosclerosis coronary artery  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  3/3348 (0.09%)  2/5777 (0.03%) 
Arteriospasm coronary  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Atrial fibrillation  1  3/2263 (0.13%)  6/2285 (0.26%)  4/2170 (0.18%)  4/3348 (0.12%)  49/5777 (0.85%) 
Atrial flutter  1  2/2263 (0.09%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  6/5777 (0.10%) 
Atrial tachycardia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Atrial thrombosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Atrioventricular block  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Atrioventricular block complete  1  1/2263 (0.04%)  1/2285 (0.04%)  2/2170 (0.09%)  4/3348 (0.12%)  4/5777 (0.07%) 
Atrioventricular block first degree  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Atrioventricular block second degree  1  1/2263 (0.04%)  4/2285 (0.18%)  2/2170 (0.09%)  4/3348 (0.12%)  2/5777 (0.03%) 
Bradyarrhythmia  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Bradycardia  1  4/2263 (0.18%)  2/2285 (0.09%)  3/2170 (0.14%)  10/3348 (0.30%)  6/5777 (0.10%) 
Cardiac aneurysm  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cardiac arrest  1  2/2263 (0.09%)  7/2285 (0.31%)  7/2170 (0.32%)  15/3348 (0.45%)  9/5777 (0.16%) 
Cardiac discomfort  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Cardiac failure  1  5/2263 (0.22%)  4/2285 (0.18%)  7/2170 (0.32%)  4/3348 (0.12%)  43/5777 (0.74%) 
Cardiac failure acute  1  2/2263 (0.09%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  16/5777 (0.28%) 
Cardiac failure chronic  1  5/2263 (0.22%)  2/2285 (0.09%)  2/2170 (0.09%)  2/3348 (0.06%)  15/5777 (0.26%) 
Cardiac failure congestive  1  4/2263 (0.18%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  30/5777 (0.52%) 
Cardiac fibrillation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Cardiac pseudoaneurysm  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cardiac tamponade  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Cardiac ventricular thrombosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Cardio-respiratory arrest  1  2/2263 (0.09%)  2/2285 (0.09%)  3/2170 (0.14%)  1/3348 (0.03%)  6/5777 (0.10%) 
Cardiogenic shock  1  1/2263 (0.04%)  3/2285 (0.13%)  3/2170 (0.14%)  7/3348 (0.21%)  9/5777 (0.16%) 
Cardiomegaly  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Cardiomyopathy  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Cardiopulmonary failure  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Conduction disorder  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Congestive cardiomyopathy  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cor pulmonale  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Coronary artery disease  1  9/2263 (0.40%)  10/2285 (0.44%)  5/2170 (0.23%)  20/3348 (0.60%)  27/5777 (0.47%) 
Coronary artery insufficiency  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Coronary artery occlusion  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  3/5777 (0.05%) 
Coronary artery stenosis  1  2/2263 (0.09%)  1/2285 (0.04%)  0/2170 (0.00%)  2/3348 (0.06%)  14/5777 (0.24%) 
Hypertensive heart disease  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Intracardiac thrombus  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ischaemic cardiomyopathy  1  3/2263 (0.13%)  5/2285 (0.22%)  2/2170 (0.09%)  4/3348 (0.12%)  6/5777 (0.10%) 
Left ventricular dysfunction  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  3/5777 (0.05%) 
Left ventricular failure  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Left ventricular hypertrophy  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Microvascular coronary artery disease  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Mitral valve incompetence  1  5/2263 (0.22%)  3/2285 (0.13%)  0/2170 (0.00%)  1/3348 (0.03%)  3/5777 (0.05%) 
Myocardial infarction  1  4/2263 (0.18%)  2/2285 (0.09%)  5/2170 (0.23%)  2/3348 (0.06%)  42/5777 (0.73%) 
Myocardial ischaemia  1  6/2263 (0.27%)  3/2285 (0.13%)  5/2170 (0.23%)  6/3348 (0.18%)  10/5777 (0.17%) 
Nodal arrhythmia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Palpitations  1  3/2263 (0.13%)  2/2285 (0.09%)  2/2170 (0.09%)  1/3348 (0.03%)  1/5777 (0.02%) 
Pericardial effusion  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Pericarditis  1  2/2263 (0.09%)  1/2285 (0.04%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Prinzmetal angina  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Pulseless electrical activity  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Right ventricular dysfunction  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Right ventricular failure  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Silent myocardial infarction  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Sinus arrest  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Sinus bradycardia  1  3/2263 (0.13%)  0/2285 (0.00%)  2/2170 (0.09%)  2/3348 (0.06%)  1/5777 (0.02%) 
Sinus node dysfunction  1  4/2263 (0.18%)  2/2285 (0.09%)  5/2170 (0.23%)  4/3348 (0.12%)  6/5777 (0.10%) 
Sinus tachycardia  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Stress cardiomyopathy  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Supraventricular tachycardia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Tachyarrhythmia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Tachycardia  1  3/2263 (0.13%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Torsade de pointes  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Tricuspid valve incompetence  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Trifascicular block  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ventricular arrhythmia  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Ventricular extrasystoles  1  1/2263 (0.04%)  0/2285 (0.00%)  2/2170 (0.09%)  2/3348 (0.06%)  1/5777 (0.02%) 
Ventricular fibrillation  1  4/2263 (0.18%)  9/2285 (0.39%)  3/2170 (0.14%)  7/3348 (0.21%)  7/5777 (0.12%) 
Ventricular tachyarrhythmia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Ventricular tachycardia  1  10/2263 (0.44%)  5/2285 (0.22%)  9/2170 (0.41%)  16/3348 (0.48%)  18/5777 (0.31%) 
Congenital, familial and genetic disorders           
Atrial septal defect  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Branchial cyst  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cerebrovascular arteriovenous malformation  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Haemorrhagic arteriovenous malformation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hereditary haemochromatosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hydrocele  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Nonketotic hyperglycinaemia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Phimosis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Pyloric stenosis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Tracheo-oesophageal fistula  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ear and labyrinth disorders           
Cerumen impaction  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ear pain  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hypoacusis  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Meniere's disease  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Otosclerosis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Presbyacusis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Sudden hearing loss  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Tympanic membrane perforation  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Vertigo  1  3/2263 (0.13%)  5/2285 (0.22%)  4/2170 (0.18%)  4/3348 (0.12%)  4/5777 (0.07%) 
Vertigo positional  1  2/2263 (0.09%)  2/2285 (0.09%)  3/2170 (0.14%)  2/3348 (0.06%)  2/5777 (0.03%) 
Endocrine disorders           
Goitre  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Hyperparathyroidism primary  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Hyperthyroidism  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hypopituitarism  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hypothyroidism  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Inappropriate antidiuretic hormone secretion  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Primary hyperaldosteronism  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Toxic goitre  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Eye disorders           
Amaurosis fugax  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Angle closure glaucoma  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Blindness  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Blindness transient  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Blindness unilateral  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cataract  1  4/2263 (0.18%)  8/2285 (0.35%)  5/2170 (0.23%)  12/3348 (0.36%)  8/5777 (0.14%) 
Cataract cortical  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cataract diabetic  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cataract nuclear  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Corneal degeneration  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Corneal infiltrates  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Dacryostenosis acquired  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Diabetic retinopathy  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  1/5777 (0.02%) 
Eye haemorrhage  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Eyelid ptosis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Glaucoma  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Iridocyclitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Lens dislocation  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Macular degeneration  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Macular fibrosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Macular hole  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Macular oedema  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Neovascular age-related macular degeneration  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Ocular ischaemic syndrome  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Papilloedema  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Retinal artery thrombosis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Retinal detachment  1  2/2263 (0.09%)  2/2285 (0.09%)  0/2170 (0.00%)  2/3348 (0.06%)  2/5777 (0.03%) 
Retinal haemorrhage  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Retinal vein occlusion  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Retinal vein thrombosis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Vitreous haemorrhage  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Gastrointestinal disorders           
Abdominal adhesions  1  0/2263 (0.00%)  0/2285 (0.00%)  2/2170 (0.09%)  1/3348 (0.03%)  1/5777 (0.02%) 
Abdominal discomfort  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Abdominal distension  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Abdominal hernia  1  3/2263 (0.13%)  1/2285 (0.04%)  2/2170 (0.09%)  0/3348 (0.00%)  0/5777 (0.00%) 
Abdominal pain  1  7/2263 (0.31%)  4/2285 (0.18%)  10/2170 (0.46%)  10/3348 (0.30%)  6/5777 (0.10%) 
Abdominal pain lower  1  0/2263 (0.00%)  1/2285 (0.04%)  2/2170 (0.09%)  0/3348 (0.00%)  0/5777 (0.00%) 
Abdominal pain upper  1  6/2263 (0.27%)  2/2285 (0.09%)  3/2170 (0.14%)  2/3348 (0.06%)  4/5777 (0.07%) 
Acute abdomen  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Alcoholic pancreatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Anal fissure  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anal haemorrhage  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anal skin tags  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anal ulcer  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Anal ulcer haemorrhage  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Anorectal disorder  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Appendiceal mucocoele  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Appendix disorder  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Ascites  1  0/2263 (0.00%)  2/2285 (0.09%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Change of bowel habit  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Chronic gastritis  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Colitis  1  3/2263 (0.13%)  3/2285 (0.13%)  2/2170 (0.09%)  3/3348 (0.09%)  4/5777 (0.07%) 
Colitis ischaemic  1  1/2263 (0.04%)  1/2285 (0.04%)  2/2170 (0.09%)  1/3348 (0.03%)  1/5777 (0.02%) 
Colitis microscopic  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Colitis ulcerative  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  3/3348 (0.09%)  0/5777 (0.00%) 
Colonic fistula  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Constipation  1  4/2263 (0.18%)  2/2285 (0.09%)  1/2170 (0.05%)  4/3348 (0.12%)  3/5777 (0.05%) 
Crohn's disease  1  1/2263 (0.04%)  3/2285 (0.13%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Dental caries  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Diabetic gastroenteropathy  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Diarrhoea  1  3/2263 (0.13%)  5/2285 (0.22%)  4/2170 (0.18%)  2/3348 (0.06%)  3/5777 (0.05%) 
Dieulafoy's vascular malformation  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Diverticulum  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  2/5777 (0.03%) 
Diverticulum intestinal  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Diverticulum intestinal haemorrhagic  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Duodenal stenosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Duodenal ulcer  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Duodenal ulcer haemorrhage  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Duodenal ulcer perforation  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Duodenitis  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Dyspepsia  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Dysphagia  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  2/3348 (0.06%)  2/5777 (0.03%) 
Enteritis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Enterocolitis  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Enterovesical fistula  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Epigastric discomfort  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Erosive duodenitis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Erosive oesophagitis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Faecaloma  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Faeces discoloured  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Flatulence  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Food poisoning  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Gallstone ileus  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastric haemorrhage  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Gastric ulcer  1  7/2263 (0.31%)  6/2285 (0.26%)  0/2170 (0.00%)  1/3348 (0.03%)  2/5777 (0.03%) 
Gastric ulcer haemorrhage  1  2/2263 (0.09%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Gastric ulcer perforation  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastric volvulus  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Gastritis  1  4/2263 (0.18%)  1/2285 (0.04%)  4/2170 (0.18%)  6/3348 (0.18%)  4/5777 (0.07%) 
Gastritis erosive  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Gastritis haemorrhagic  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastroduodenitis  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastrointestinal angiodysplasia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastrointestinal disorder  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Gastrointestinal erosion  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Gastrointestinal haemorrhage  1  13/2263 (0.57%)  16/2285 (0.70%)  14/2170 (0.65%)  13/3348 (0.39%)  5/5777 (0.09%) 
Gastrointestinal necrosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Gastrointestinal pain  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastrointestinal perforation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Gastrointestinal ulcer  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gastrointestinal vascular malformation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Gastrooesophageal reflux disease  1  1/2263 (0.04%)  5/2285 (0.22%)  1/2170 (0.05%)  4/3348 (0.12%)  4/5777 (0.07%) 
Haematemesis  1  1/2263 (0.04%)  1/2285 (0.04%)  2/2170 (0.09%)  2/3348 (0.06%)  3/5777 (0.05%) 
Haematochezia  1  1/2263 (0.04%)  3/2285 (0.13%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Haemorrhagic necrotic pancreatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Haemorrhoidal haemorrhage  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Haemorrhoids  1  2/2263 (0.09%)  3/2285 (0.13%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Haemorrhoids thrombosed  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hiatus hernia  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Ileal ulcer  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Ileus  1  3/2263 (0.13%)  1/2285 (0.04%)  2/2170 (0.09%)  3/3348 (0.09%)  2/5777 (0.03%) 
Ileus paralytic  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Impaired gastric emptying  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  3/3348 (0.09%)  0/5777 (0.00%) 
Incarcerated inguinal hernia  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Incarcerated umbilical hernia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Inflammatory bowel disease  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  2/5777 (0.03%) 
Inguinal hernia  1  8/2263 (0.35%)  5/2285 (0.22%)  7/2170 (0.32%)  7/3348 (0.21%)  8/5777 (0.14%) 
Inguinal hernia strangulated  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Intestinal fistula  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Intestinal haemorrhage  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Intestinal infarction  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Intestinal ischaemia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  2/5777 (0.03%) 
Intestinal mass  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Intestinal obstruction  1  2/2263 (0.09%)  1/2285 (0.04%)  3/2170 (0.14%)  2/3348 (0.06%)  2/5777 (0.03%) 
Intestinal perforation  1  2/2263 (0.09%)  1/2285 (0.04%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Intestinal ulcer  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Irritable bowel syndrome  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Ischaemic enteritis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Large intestinal obstruction  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Large intestinal stenosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Large intestine perforation  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Large intestine polyp  1  3/2263 (0.13%)  4/2285 (0.18%)  2/2170 (0.09%)  12/3348 (0.36%)  6/5777 (0.10%) 
Lower gastrointestinal haemorrhage  1  1/2263 (0.04%)  4/2285 (0.18%)  1/2170 (0.05%)  0/3348 (0.00%)  2/5777 (0.03%) 
Mallory-Weiss syndrome  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  1/5777 (0.02%) 
Melaena  1  2/2263 (0.09%)  1/2285 (0.04%)  0/2170 (0.00%)  2/3348 (0.06%)  3/5777 (0.05%) 
Mesenteric artery stenosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Mesenteric artery thrombosis  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Mesenteric vascular insufficiency  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Mouth cyst  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Mouth ulceration  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Narcotic bowel syndrome  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Nausea  1  4/2263 (0.18%)  3/2285 (0.13%)  2/2170 (0.09%)  4/3348 (0.12%)  0/5777 (0.00%) 
Obstruction gastric  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Odynophagia  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Oesophageal obstruction  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Oesophageal perforation  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Oesophageal rupture  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Oesophageal stenosis  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Oesophageal ulcer  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Oesophageal varices haemorrhage  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Oesophagitis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Pancreatic cyst  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Pancreatic disorder  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pancreatic duct dilatation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pancreatic mass  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pancreatic pseudocyst  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Pancreatitis  1  6/2263 (0.27%)  6/2285 (0.26%)  3/2170 (0.14%)  11/3348 (0.33%)  3/5777 (0.05%) 
Pancreatitis acute  1  3/2263 (0.13%)  6/2285 (0.26%)  2/2170 (0.09%)  3/3348 (0.09%)  6/5777 (0.10%) 
Pancreatitis chronic  1  0/2263 (0.00%)  2/2285 (0.09%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Pancreatitis necrotising  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Peptic ulcer  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  3/3348 (0.09%)  0/5777 (0.00%) 
Peptic ulcer haemorrhage  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Peritoneal haemorrhage  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pneumatosis intestinalis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Pneumoperitoneum  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Proctalgia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Proctitis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ranula  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Rectal haemorrhage  1  1/2263 (0.04%)  6/2285 (0.26%)  1/2170 (0.05%)  1/3348 (0.03%)  3/5777 (0.05%) 
Rectal lesion  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Rectal perforation  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Rectal polyp  1  1/2263 (0.04%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Retroperitoneal haematoma  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Retroperitoneal haemorrhage  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Salivary gland calculus  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Small intestinal haemorrhage  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Small intestinal obstruction  1  2/2263 (0.09%)  1/2285 (0.04%)  2/2170 (0.09%)  1/3348 (0.03%)  9/5777 (0.16%) 
Small intestinal perforation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Small intestine ulcer  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Subileus  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Thrombosis mesenteric vessel  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Umbilical hernia  1  1/2263 (0.04%)  4/2285 (0.18%)  2/2170 (0.09%)  4/3348 (0.12%)  0/5777 (0.00%) 
Upper gastrointestinal haemorrhage  1  3/2263 (0.13%)  8/2285 (0.35%)  8/2170 (0.37%)  8/3348 (0.24%)  3/5777 (0.05%) 
Vomiting  1  5/2263 (0.22%)  4/2285 (0.18%)  2/2170 (0.09%)  4/3348 (0.12%)  0/5777 (0.00%) 
General disorders           
Adverse drug reaction  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Asthenia  1  4/2263 (0.18%)  2/2285 (0.09%)  1/2170 (0.05%)  3/3348 (0.09%)  3/5777 (0.05%) 
Cardiac death  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  4/5777 (0.07%) 
Chest discomfort  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Chest pain  1  3/2263 (0.13%)  12/2285 (0.53%)  2/2170 (0.09%)  9/3348 (0.27%)  9/5777 (0.16%) 
Chills  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Complication associated with device  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Death  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  4/3348 (0.12%)  12/5777 (0.21%) 
Drowning  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Drug intolerance  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Exercise tolerance decreased  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Facial pain  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Fatigue  1  2/2263 (0.09%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gait disturbance  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
General physical health deterioration  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  2/5777 (0.03%) 
Generalised oedema  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Hernia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  2/5777 (0.03%) 
Heteroplasia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Hyperplasia  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Hypothermia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Impaired healing  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  0/5777 (0.00%) 
Implant site irritation  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Incarcerated hernia  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Inflammation  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Influenza like illness  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Injection site reaction  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Ischaemic ulcer  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Local swelling  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Malaise  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Mass  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Multiple organ dysfunction syndrome  1  3/2263 (0.13%)  2/2285 (0.09%)  0/2170 (0.00%)  3/3348 (0.09%)  6/5777 (0.10%) 
Necrosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Non-cardiac chest pain  1  44/2263 (1.94%)  48/2285 (2.10%)  39/2170 (1.80%)  75/3348 (2.24%)  35/5777 (0.61%) 
Oedema peripheral  1  2/2263 (0.09%)  0/2285 (0.00%)  1/2170 (0.05%)  3/3348 (0.09%)  1/5777 (0.02%) 
Pacemaker syndrome  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pain  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Polyp  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Pseudocyst  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Pyrexia  1  4/2263 (0.18%)  4/2285 (0.18%)  6/2170 (0.28%)  5/3348 (0.15%)  3/5777 (0.05%) 
Stent-graft endoleak  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  1/5777 (0.02%) 
Sudden cardiac death  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  11/5777 (0.19%) 
Sudden death  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  7/5777 (0.12%) 
Surgical failure  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Systemic inflammatory response syndrome  1  1/2263 (0.04%)  0/2285 (0.00%)  3/2170 (0.14%)  2/3348 (0.06%)  0/5777 (0.00%) 
Vascular stent restenosis  1  2/2263 (0.09%)  2/2285 (0.09%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Vascular stent stenosis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  3/5777 (0.05%) 
Vascular stent thrombosis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Vessel puncture site haemorrhage  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatobiliary disorders           
Acute hepatic failure  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Alcoholic liver disease  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Autoimmune hepatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Bile duct stenosis  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Bile duct stone  1  4/2263 (0.18%)  0/2285 (0.00%)  1/2170 (0.05%)  2/3348 (0.06%)  1/5777 (0.02%) 
Biliary cirrhosis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Biliary colic  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Biliary dilatation  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Biliary fistula  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cholangitis  1  2/2263 (0.09%)  2/2285 (0.09%)  4/2170 (0.18%)  0/3348 (0.00%)  0/5777 (0.00%) 
Cholangitis acute  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Cholecystitis  1  11/2263 (0.49%)  4/2285 (0.18%)  8/2170 (0.37%)  9/3348 (0.27%)  7/5777 (0.12%) 
Cholecystitis acute  1  5/2263 (0.22%)  7/2285 (0.31%)  4/2170 (0.18%)  7/3348 (0.21%)  5/5777 (0.09%) 
Cholelithiasis  1  8/2263 (0.35%)  8/2285 (0.35%)  8/2170 (0.37%)  18/3348 (0.54%)  4/5777 (0.07%) 
Cholestasis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Drug-induced liver injury  1  0/2263 (0.00%)  1/2285 (0.04%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Gallbladder polyp  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Haemorrhagic hepatic cyst  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatic cirrhosis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  4/5777 (0.07%) 
Hepatic congestion  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hepatic failure  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hepatic function abnormal  1  1/2263 (0.04%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatic steatosis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hepatic vein thrombosis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatitis toxic  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hepatomegaly  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hepatorenal failure  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Hepatosplenomegaly  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hydrocholecystis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Ischaemic hepatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Jaundice cholestatic  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  1/3348 (0.03%)  2/5777 (0.03%) 
Liver disorder  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Liver injury  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Non-alcoholic fatty liver  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Non-alcoholic steatohepatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Portal vein thrombosis  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Steatohepatitis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Immune system disorders           
Allergy to arthropod sting  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Anaphylactic reaction  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anaphylactic shock  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  2/5777 (0.03%) 
Contrast media allergy  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Drug hypersensitivity  1  0/2263 (0.00%)  0/2285 (0.00%)  2/2170 (0.09%)  0/3348 (0.00%)  0/5777 (0.00%) 
Hypersensitivity  1  0/2263 (0.00%)  1/2285 (0.04%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Infections and infestations           
Abdominal abscess  1  2/2263 (0.09%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Abdominal infection  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Abdominal sepsis  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Abscess intestinal  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Abscess jaw  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Abscess limb  1  4/2263 (0.18%)  1/2285 (0.04%)  3/2170 (0.14%)  3/3348 (0.09%)  0/5777 (0.00%) 
Abscess neck  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%) 
Abscess oral  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  1/3348 (0.03%)  0/5777 (0.00%) 
Abscess soft tissue  1  0/2263 (0.00%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  1/5777 (0.02%) 
Acute hepatitis B  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  0/5777 (0.00%) 
Acute sinusitis  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  0/3348 (0.00%)  0/5777 (0.00%) 
Anal abscess  1  1/2263 (0.04%)  1/2285 (0.04%)  1/2170 (0.05%)  2/3348 (0.06%)  2/5777 (0.03%) 
Appendicitis  1  3/2263 (0.13%)  4/2285 (0.18%)  6/2170 (0.28%)  4/3348 (0.12%)  3/5777 (0.05%) 
Appendicitis perforated  1  0/2263 (0.00%)  0/2285 (0.00%)  1/2170 (0.05%)  0/3348 (0.00%)  1/5777 (0.02%) 
Arthritis bacterial  1  1/2263 (0.04%)  1/2285 (0.04%)  0/2170 (0.00%)  1/3348 (0.03%)  1/5777 (0.02%) 
Arthritis infective  1  1/2263 (0.04%)  0/2285 (0.00%)  0/2170 (0.00%)  3/3348 (0.09%)  1/5777 (0.02%) 
Atypical pneumonia  1  0/2263 (0.00%)  2/2285 (0.09%)  0/2170 (0.00%)  2/3348 (0.06%)  0/5777 (0.00%)