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A Study to Evaluate the Effect of Long-term Treatment With BELVIQ (Lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors (CAMELLIA-TIMI)

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: NCT02019264
Recruitment Status : Completed
First Posted : December 24, 2013
Results First Posted : July 16, 2019
Last Update Posted : July 16, 2019
Sponsor:
Collaborator:
Thrombolysis In Myocardial Infarction (TIMI) Academic Research Organization
Information provided by (Responsible Party):
Eisai Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Cardiovascular Disease
High Cardiovascular Risk
Obesity
Overweight
Type 2 Diabetes
Interventions Drug: Lorcaserin hydrochloride
Drug: Placebo
Enrollment 14673
Recruitment Details Participants took part in the study at investigative sites in the United States, Bahamas, Canada, Mexico, Chile, New Zealand, Poland, and Australia from 24 Jan 2014 to 14 May 2018.
Pre-assignment Details A total of 14,673 participants were screened and enrolled, of which 2673 participants were screen failures and 12,000 were randomized to receive lorcaserin hydrochloride (HCl) or placebo.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months. Participants received lorcaserin HCL 10 milligram (mg), tablets, orally, twice daily for up to 52 months.
Period Title: Overall Study
Started 6000 6000
Safety Analysis Set 5992 5995
Completed [1] 5752 5793
Not Completed 248 207
Reason Not Completed
Not treated             6             4
Lost to Follow-up             50             47
Withdrawal by Subject             142             117
Administrative reason             36             28
Missing             14             11
[1]
Participants who died on trial were considered completed.
Arm/Group Title Placebo Lorcaserin 10 mg Total
Hide Arm/Group Description Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months. Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months. Total of all reporting groups
Overall Number of Baseline Participants 6000 6000 12000
Hide Baseline Analysis Population Description
The full analysis (FA) set included all randomized participants regardless of whether they took study drug or not.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6000 participants 6000 participants 12000 participants
63.7  (8.31) 63.5  (8.33) 63.6  (8.32)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6000 participants 6000 participants 12000 participants
Female
2186
  36.4%
2112
  35.2%
4298
  35.8%
Male
3814
  63.6%
3888
  64.8%
7702
  64.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6000 participants 6000 participants 12000 participants
Hispanic or Latino
536
   8.9%
502
   8.4%
1038
   8.6%
Not Hispanic or Latino
5464
  91.1%
5498
  91.6%
10962
  91.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6000 participants 6000 participants 12000 participants
American Indian or Alaska Native
21
   0.4%
26
   0.4%
47
   0.4%
Asian
74
   1.2%
85
   1.4%
159
   1.3%
Native Hawaiian or Other Pacific Islander
23
   0.4%
30
   0.5%
53
   0.4%
Black or African American
466
   7.8%
454
   7.6%
920
   7.7%
White
5331
  88.9%
5309
  88.5%
10640
  88.7%
More than one race
85
   1.4%
96
   1.6%
181
   1.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis
Hide Description The MACE events involved myocardial infarction (MI), stroke, or cardiovascular (CV) death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to Month 42
Hide Outcome Measure Data
Hide Analysis Population Description
The total time analysis set using the intent-to-treat (ITT) set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following sponsor notification of study completion, whichever occurred first.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 6000 6000
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates. MACE met non-inferiority when the one-sided upper bound of 97.5% confidence interval of the HR was less than 1.4 (the non-inferiority margin).
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.005
Confidence Interval (2-Sided) 97.5%
0.842 to 1.198
Estimation Comments [Not Specified]
2.Primary Outcome
Title Time From Randomization to First Occurrence of MACE+
Hide Description The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The total time analysis set used the ITT set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following Sponsor Notification of Study Completion, whichever occurred first.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 6000 6000
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.5464
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.969
Confidence Interval (2-Sided) 95%
0.873 to 1.074
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline
Hide Description Time from randomization to conversion to T2DM was defined as first occurrence of any component of the 2013 American Diabetes Association (ADA) Diagnostic Criteria (ADA, 2013) in participants with prediabetes at baseline. The diagnostic criteria were met if a participant had unequivocal hyperglycemia (random plasma glucose greater than or equal to (>=) 200 milligram per deciliter (mg/dL) (11.1 millimole per liter [mmol/L]) with classic symptoms of hyperglycemia or hyperglycemic crisis) or any of the following criteria were observed and subsequently confirmed on repeat laboratory testing such as: glycosylated hemoglobin (HbA1c) >=to 6.5%; fasting plasma glucose (FPG) >=126 mg/dL (7.0 mmol/L); 2-hour plasma glucose >=200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT). The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
Prediabetes and total time analysis set used ITT set: without a history of any type of diabetes and who were prediabetic at baseline; events were counted that occurred while participants were on, off treatment; participants with no events were censored at last study contact/at visit after notification of study completion, whichever occurred first.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 1976 2015
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on Cox-regression model including treatment as covariate.
Statistical Test of Hypothesis P-Value 0.0380
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.807
Confidence Interval (2-Sided) 95%
0.659 to 0.988
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time From Randomization to First Occurrence of the Individual Components of MACE+
Hide Description The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or HF, or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The total time analysis set used the ITT set, events counted occurred while participants were on and off treatment. Participants with no events were censored at last study contact or at the visit following Sponsor Notification of Study Completion, whichever first.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 6000 6000
Mean (95% Confidence Interval)
Unit of Measure: days
MI
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
Stroke
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
CV death
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
Hospitalization for unstable angina
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
HF
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
Coronary revascularization
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Myocardial Infarction: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates. 97.5% confidence interval refers to the upper limit of the displayed 2-sided 95% confidence interval.
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.991
Confidence Interval (2-Sided) 97.5%
0.824 to 1.191
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Time to Stroke: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates. 97.5% CI refers to the upper limit of the displayed 2-sided 95% CI.
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.856
Confidence Interval (2-Sided) 97.5%
0.639 to 1.145
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Cardiovascular Death: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates. 97.5% confidence interval refers to the upper limit of the displayed 2-sided 95% confidence interval.
Statistical Test of Hypothesis P-Value 0.0262
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.045
Confidence Interval (2-Sided) 97.5%
0.778 to 1.404
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hospitalization for Unstable Angina: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.3243
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.163
Confidence Interval (2-Sided) 95%
0.861 to 1.571
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Heart Failure: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.6758
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.952
Confidence Interval (2-Sided) 95%
0.757 to 1.197
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Coronary Revascularization: Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.7817
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.981
Confidence Interval (2-Sided) 95%
0.856 to 1.125
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time From Randomization to Event of All-cause Mortality
Hide Description The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The total time analysis set used the ITT set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following Sponsor Notification of Study Completion, whichever occurred first.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 6000 6000
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.4212
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.082
Confidence Interval (2-Sided) 95%
0.893 to 1.310
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline
Hide Description Normal glucose homeostasis was defined as HbA1c less than or equal to (<=) 5.6% and FPG < 100 mg/dL without any antidiabetic treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The prediabetes analysis set included all participants in the ITT set without a history of any type of diabetes and who were prediabetic at baseline.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 1976 2015
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on a Cox regression model including treatment as covariate.
Statistical Test of Hypothesis P-Value 0.1810
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.124
Confidence Interval (2-Sided) 95%
0.947 to 1.333
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline
Hide Description The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The nondiabetes analysis set included all participants in the ITT set without a history of any type of diabetes at baseline.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 2569 2615
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on a Cox regression model including treatment as covariate.
Statistical Test of Hypothesis P-Value 0.0116
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.773
Confidence Interval (2-Sided) 95%
0.633 to 0.944
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline
Hide Description [Not Specified]
Time Frame Baseline, and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
The T2DM analysis set included all participants in the ITT set who had T2DM at baseline. The T2DM analysis set where data was available at specified time points.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 3403 3362
Mean (Standard Deviation)
Unit of Measure: percentage of HbA1c
Baseline Number Analyzed 3403 participants 3362 participants
6.99  (1.066) 7.01  (1.082)
Change at Month 6 Number Analyzed 3087 participants 3035 participants
0.06  (0.777) -0.33  (0.785)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value was based on analysis of covariance (ANCOVA) model with treatment and stratification variable (presence of established CV disease or CV risk factors without established CV disease) as factors, and baseline HbA1c, as a covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least square (LS) Mean Difference (Net)
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-0.43 to -0.35
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants
Hide Description New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (albumin-to-creatinine ratio [ACR] >=30mcg/mg and ACR>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at Baseline developed macroalbuminuria, ACR increased >=30% from Baseline during treatment), newly developed chronic kidney disease (CKD) (eGFR >=90 milliliter per minute per 1.73 [mL/min/1.73]body surface area (BSA) and without kidney damage at Baseline changed to CKD Stage 1/higher as per National Kidney Foundation [NKF] Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times Baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT set included all randomized participants regardless of whether they took study drug or not. This set was the same as the full analysis set.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 6000 6000
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.0054
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.869
Confidence Interval (2-Sided) 95%
0.787 to 0.959
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline
Hide Description New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR >=30mcg/mg and ACR >=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased >=30% from baseline during treatment), CKD (eGFR >=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The prediabetes analysis set included all participants in the ITT set without a history of any type of diabetes and who were prediabetic at baseline.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 1976 2015
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio on a Cox regression model including treatment as covariate.
Statistical Test of Hypothesis P-Value 0.3661
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.904
Confidence Interval (2-Sided) 95%
0.727 to 1.125
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline
Hide Description New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR >=30 mcg/mg and ACR >=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased >=30% from baseline during treatment), CKD (eGFR >=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The T2DM analysis set included all participants in the ITT set who had T2DM at baseline.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 3403 3362
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0082
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.855
Confidence Interval (2-Sided) 95%
0.762 to 0.960
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline
Hide Description Improvement in renal function was defined as first occurrence of regression of albuminuria or regression of CKD. Regression of albuminuria was defined as when participants with macroalbuminuria at baseline developed microalbuminuria or nonalbuminuria (ACR <30 mcg/mg in spot urine), or participants with microalbuminuria at baseline became nonalbuminuric, and ACR value decreased >= 30% from previous assessment during treatment. Regression of CKD defined as when participants with CKD Stage 1 or higher at baseline improved to normal or lower stages by NKF guidelines (eGFR >=90 with albuminuria at baseline improved to eGFR >=90 without albuminuria, or eGFR 60 to 89 at baseline became eGFR >=90 with or without albuminuria, or eGFR between 30 to 59 at baseline improved to >60 mL/min/1.73 BSA) during treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time Frame Baseline up to end of study (Month 56)
Hide Outcome Measure Data
Hide Analysis Population Description
The T2DM analysis set included all participants in the ITT set who had T2DM at baseline.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 3403 3362
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time and 95% confidence interval could not be calculated since quartile was not estimable due to higher number of censored participants.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Hazard ratio was based on Cox-regression model including treatment and CV strata as covariates.
Statistical Test of Hypothesis P-Value 0.0297
Comments [Not Specified]
Method Primary Analytic Method
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.182
Confidence Interval (2-Sided) 95%
1.017 to 1.375
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes
Hide Description [Not Specified]
Time Frame Months 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
The FDA-defined valvulopathy analysis set included all participants in the ITT set without FDA-defined valvulopathy at baseline. The FDA-defined valvulopathy analysis set where data was available at specified time point.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 1935 1925
Measure Type: Number
Unit of Measure: percentage of participants
Month 6 Number Analyzed 1683 participants 1681 participants
1.4 2.1
Month 12 Number Analyzed 1564 participants 1579 participants
1.5 1.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5015
Comments P-value was based on logistic regression including treatment as a factor and baseline body mass index (BMI) as a covariate.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.21
Confidence Interval (2-Sided) 95%
0.69 to 2.11
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy
Hide Description [Not Specified]
Time Frame Months 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set in participants with FDA-defined valvulopathy at baseline was used. The ITT analysis set in participants with FDA-defined valvulopathy at baseline where data was available at specified time point.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 228 225
Measure Type: Number
Unit of Measure: percentage of participants
Month 6 Number Analyzed 194 participants 201 participants
2.1 3.5
Month 12 Number Analyzed 180 participants 189 participants
1.7 2.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7249
Comments P-value was based on logistic regression including treatment as a factor and baseline BMI as a covariate.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.31
Confidence Interval (2-Sided) 95%
0.29 to 5.98
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure
Hide Description [Not Specified]
Time Frame Baseline, Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set-participants in ECHO substudy included all randomized participants regardless of whether they took study drug or not. The ITT analysis set-participants in the ECHO substudy, where data was available at specified time points.
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description:
Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months.
Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months.
Overall Number of Participants Analyzed 2167 2151
Mean (Standard Deviation)
Unit of Measure: Millimeter of mercury (mmHg)
Baseline Number Analyzed 1368 participants 1358 participants
26.4354  (7.66312) 26.2029  (7.54123)
Change at Month 12 Number Analyzed 882 participants 893 participants
-0.6418  (6.81716) -0.8223  (7.23770)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Lorcaserin 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2976
Comments P value was based on a mixed-effects model (unstructured covariance matrix) with repeated measures with treatment, month and treatment by month interaction as factors and baseline pulmonary arterial systolic pressure and baseline BMI as covariates.
Method Mixed-effects model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least square (LS) Mean Difference (Net)
Estimated Value -0.9036
Confidence Interval (2-Sided) 95%
-1.2908 to -0.5163
Estimation Comments [Not Specified]
Time Frame From baseline up to 30 days after last dose of study drug (approximately 56 months)
Adverse Event Reporting Description Adverse events were collected for the participants who were in the safety analysis set (all participants who received at least 1 dose of study drug and had at least one post dose safety assessment).
 
Arm/Group Title Placebo Lorcaserin 10 mg
Hide Arm/Group Description Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months. Participants received lorcaserin HCL 10 milligram (mg), tablets, orally, twice daily for up to 52 months.
All-Cause Mortality
Placebo Lorcaserin 10 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   202/5992 (3.37%)      219/5995 (3.65%)    
Hide Serious Adverse Events
Placebo Lorcaserin 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2021/5992 (33.73%)      1974/5995 (32.93%)    
Blood and lymphatic system disorders     
Abdominal lymphadenopathy † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Anaemia † 1  19/5992 (0.32%)  19 12/5995 (0.20%)  14
Anaemia macrocytic † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Autoimmune haemolytic anaemia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Disseminated intravascular coagulation † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Febrile neutropenia † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  3
Haemorrhagic anaemia † 1  7/5992 (0.12%)  7 3/5995 (0.05%)  3
Iron deficiency anaemia † 1  2/5992 (0.03%)  2 4/5995 (0.07%)  4
Leukocytosis † 1  3/5992 (0.05%)  3 5/5995 (0.08%)  5
Leukopenia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Lymphadenopathy † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Microcytic anaemia † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Neutropenia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Normochromic normocytic anaemia † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Splenic haematoma † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Splenic infarction † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Spontaneous haematoma † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Thrombocytopenia † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Cardiac disorders     
Acute coronary syndrome † 1  14/5992 (0.23%)  14 11/5995 (0.18%)  11
Acute left ventricular failure † 1  3/5992 (0.05%)  3 3/5995 (0.05%)  3
Acute myocardial infarction † 1  117/5992 (1.95%)  131 105/5995 (1.75%)  118
Angina pectoris † 1  123/5992 (2.05%)  136 142/5995 (2.37%)  152
Angina unstable † 1  106/5992 (1.77%)  115 113/5995 (1.88%)  129
Anginal equivalent † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Aortic valve disease † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Aortic valve incompetence † 1  4/5992 (0.07%)  4 6/5995 (0.10%)  6
Aortic valve stenosis † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Arrhythmia † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Arteriosclerosis coronary artery † 1  1/5992 (0.02%)  1 9/5995 (0.15%)  9
Arteriospasm coronary † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Atrial fibrillation † 1  102/5992 (1.70%)  122 105/5995 (1.75%)  120
Atrial flutter † 1  22/5992 (0.37%)  28 21/5995 (0.35%)  23
Atrial tachycardia † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Atrioventricular block † 1  0/5992 (0.00%)  0 4/5995 (0.07%)  4
Atrioventricular block complete † 1  7/5992 (0.12%)  7 4/5995 (0.07%)  4
Atrioventricular block first degree † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Atrioventricular block second degree † 1  3/5992 (0.05%)  3 7/5995 (0.12%)  7
Bradyarrhythmia † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Bradycardia † 1  17/5992 (0.28%)  17 18/5995 (0.30%)  18
Bundle branch block bilateral † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Bundle branch block left † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Bundle branch block right † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Cardiac aneurysm † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cardiac arrest † 1  19/5992 (0.32%)  19 17/5995 (0.28%)  17
Cardiac discomfort † 1  7/5992 (0.12%)  7 3/5995 (0.05%)  3
Cardiac disorder † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Cardiac failure † 1  21/5992 (0.35%)  25 18/5995 (0.30%)  19
Cardiac failure acute † 1  5/5992 (0.08%)  6 3/5995 (0.05%)  3
Cardiac failure chronic † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Cardiac failure congestive † 1  106/5992 (1.77%)  139 91/5995 (1.52%)  124
Cardiac perforation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cardiac tamponade † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Cardiac valve disease † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Cardiac ventricular thrombosis † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Cardio-respiratory arrest † 1  6/5992 (0.10%)  6 7/5995 (0.12%)  7
Cardiogenic shock † 1  5/5992 (0.08%)  5 4/5995 (0.07%)  4
Cardiomyopathy † 1  4/5992 (0.07%)  4 5/5995 (0.08%)  5
Cardiopulmonary failure † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Cardiovascular disorder † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Cardiovascular insufficiency † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cor pulmonale † 1  1/5992 (0.02%)  1 3/5995 (0.05%)  3
Cor pulmonale acute † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Cor pulmonale chronic † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Coronary artery disease † 1  78/5992 (1.30%)  80 87/5995 (1.45%)  92
Coronary artery occlusion † 1  6/5992 (0.10%)  6 8/5995 (0.13%)  10
Coronary artery perforation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Coronary artery stenosis † 1  13/5992 (0.22%)  13 17/5995 (0.28%)  17
Diastolic dysfunction † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hyperdynamic left ventricle † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hypertensive heart disease † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Intracardiac thrombus † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Ischaemic cardiomyopathy † 1  4/5992 (0.07%)  4 3/5995 (0.05%)  3
Kounis syndrome † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Left atrial dilatation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Left ventricular dysfunction † 1  3/5992 (0.05%)  3 3/5995 (0.05%)  3
Left ventricular failure † 1  2/5992 (0.03%)  3 0/5995 (0.00%)  0
Microvascular coronary artery disease † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  13
Mitral valve disease † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Mitral valve incompetence † 1  12/5992 (0.20%)  12 12/5995 (0.20%)  12
Mitral valve prolapse † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Mitral valve stenosis † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Myocardial infarction † 1  31/5992 (0.52%)  31 36/5995 (0.60%)  38
Myocardial ischaemia † 1  16/5992 (0.27%)  17 14/5995 (0.23%)  14
Palpitations † 1  5/5992 (0.08%)  5 6/5995 (0.10%)  6
Pericardial cyst † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pericardial effusion † 1  0/5992 (0.00%)  0 4/5995 (0.07%)  6
Pericardial haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pericarditis † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Pericarditis constrictive † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Prinzmetal angina † 1  2/5992 (0.03%)  3 3/5995 (0.05%)  3
Pulmonary valve incompetence † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Pulseless electrical activity † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Right ventricular failure † 1  1/5992 (0.02%)  1 3/5995 (0.05%)  3
Sinus bradycardia † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Sinus node dysfunction † 1  6/5992 (0.10%)  6 15/5995 (0.25%)  17
Sinus tachycardia † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Stress cardiomyopathy † 1  0/5992 (0.00%)  0 3/5995 (0.05%)  3
Supraventricular tachycardia † 1  9/5992 (0.15%)  9 11/5995 (0.18%)  11
Systolic dysfunction † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Tachycardia † 1  1/5992 (0.02%)  1 5/5995 (0.08%)  5
Tricuspid valve incompetence † 1  7/5992 (0.12%)  7 6/5995 (0.10%)  6
Ventricular arrhythmia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Ventricular extrasystoles † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Ventricular fibrillation † 1  8/5992 (0.13%)  8 3/5995 (0.05%)  4
Ventricular tachyarrhythmia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Ventricular tachycardia † 1  22/5992 (0.37%)  27 13/5995 (0.22%)  14
Congenital, familial and genetic disorders     
Atrial septal defect † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  3
Choledochal cyst † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Developmental hip dysplasia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Gastrointestinal arteriovenous malformation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hydrocele † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hypertrophic cardiomyopathy † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Microgenia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Ear and labyrinth disorders     
Tympanic membrane perforation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Vertigo † 1  8/5992 (0.13%)  8 9/5995 (0.15%)  9
Vertigo positional † 1  1/5992 (0.02%)  1 5/5995 (0.08%)  5
Endocrine disorders     
Adrenal insufficiency † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Goitre † 1  1/5992 (0.02%)  1 5/5995 (0.08%)  5
Hyperparathyroidism † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hyperthyroidism † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hypothyroidism † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Thyroid mass † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Thyrotoxic crisis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Eye disorders     
Cataract † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Charles Bonnet syndrome † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Deformity of orbit † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Macular oedema † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Oscillopsia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Retinal artery occlusion † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Retinal vascular thrombosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Vision blurred † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Vitreous adhesions † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Vitreous haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Gastrointestinal disorders     
Abdominal adhesions † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Abdominal discomfort † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Abdominal distension † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Abdominal fat apron † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Abdominal hernia † 1  10/5992 (0.17%)  10 7/5995 (0.12%)  7
Abdominal hernia obstructive † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Abdominal incarcerated hernia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Abdominal pain † 1  11/5992 (0.18%)  11 9/5995 (0.15%)  9
Abdominal pain upper † 1  7/5992 (0.12%)  7 6/5995 (0.10%)  6
Abdominal wall haematoma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Anal fissure † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Anal incontinence † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Anorectal varices † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Ascites † 1  2/5992 (0.03%)  3 0/5995 (0.00%)  0
Coeliac artery stenosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Colitis † 1  8/5992 (0.13%)  8 4/5995 (0.07%)  4
Colitis ischaemic † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Colitis microscopic † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Colitis ulcerative † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Colonic pseudo-obstruction † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Constipation † 1  6/5992 (0.10%)  7 8/5995 (0.13%)  9
Crohn's disease † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Diarrhoea † 1  6/5992 (0.10%)  6 8/5995 (0.13%)  8
Dieulafoy's vascular malformation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Diverticular perforation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Diverticulum † 1  4/5992 (0.07%)  4 6/5995 (0.10%)  6
Diverticulum intestinal haemorrhagic † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Duodenal ulcer † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Duodenal ulcer haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Duodenal ulcer perforation † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Duodenitis † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Duodenogastric reflux † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Dyspepsia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Dysphagia † 1  6/5992 (0.10%)  6 4/5995 (0.07%)  4
Enteritis † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Enterocele † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Erosive duodenitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Erosive oesophagitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Faecaloma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Food poisoning † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Gastric antral vascular ectasia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastric disorder † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastric haemorrhage † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastric perforation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Gastric polyps † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastric ulcer † 1  5/5992 (0.08%)  5 5/5995 (0.08%)  5
Gastric ulcer haemorrhage † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Gastritis † 1  6/5992 (0.10%)  7 6/5995 (0.10%)  6
Gastritis erosive † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Gastrointestinal angiodysplasia haemorrhagic † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastrointestinal haemorrhage † 1  27/5992 (0.45%)  30 29/5995 (0.48%)  29
Gastrointestinal necrosis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Gastrointestinal ulcer haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Gastrooesophageal reflux disease † 1  9/5992 (0.15%)  10 11/5995 (0.18%)  11
Haematochezia † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Haemorrhoidal haemorrhage † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Haemorrhoids † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Hiatus hernia † 1  5/5992 (0.08%)  5 1/5995 (0.02%)  1
Ileus † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Impaired gastric emptying † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Incarcerated umbilical hernia † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Inguinal hernia † 1  9/5992 (0.15%)  9 1/5995 (0.02%)  1
Intestinal dilatation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Intestinal haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Intestinal ischaemia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Intestinal obstruction † 1  3/5992 (0.05%)  3 7/5995 (0.12%)  7
Intestinal perforation † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Intra-abdominal haematoma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Irritable bowel syndrome † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Large intestinal haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Large intestinal ulcer † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Large intestine perforation † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Large intestine polyp † 1  2/5992 (0.03%)  3 5/5995 (0.08%)  5
Lower gastrointestinal haemorrhage † 1  9/5992 (0.15%)  9 2/5995 (0.03%)  2
Megacolon † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Melaena † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Mesenteric artery stenosis † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Mesenteric panniculitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Nausea † 1  3/5992 (0.05%)  3 8/5995 (0.13%)  8
Obstruction gastric † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Odynophagia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Oesophageal food impaction † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Oesophageal pain † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Oesophageal spasm † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Oesophageal stenosis † 1  1/5992 (0.02%)  2 1/5995 (0.02%)  1
Oesophageal varices haemorrhage † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Oesophagitis † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Omental infarction † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pancreatitis † 1  14/5992 (0.23%)  15 13/5995 (0.22%)  14
Pancreatitis acute † 1  15/5992 (0.25%)  17 9/5995 (0.15%)  9
Pancreatitis chronic † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Pancreatitis relapsing † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Peptic ulcer † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Peptic ulcer haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Rectal haemorrhage † 1  6/5992 (0.10%)  6 8/5995 (0.13%)  8
Rectal polyp † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Retroperitoneal haemorrhage † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Salivary gland mass † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Small intestinal obstruction † 1  18/5992 (0.30%)  22 11/5995 (0.18%)  16
Tongue disorder † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Umbilical hernia † 1  7/5992 (0.12%)  7 6/5995 (0.10%)  6
Upper gastrointestinal haemorrhage † 1  5/5992 (0.08%)  5 3/5995 (0.05%)  3
Uvulitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Visceroptosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Vomiting † 1  7/5992 (0.12%)  7 6/5995 (0.10%)  7
General disorders     
Adverse drug reaction † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Asthenia † 1  5/5992 (0.08%)  5 9/5995 (0.15%)  10
Cardiac death † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Chest discomfort † 1  7/5992 (0.12%)  7 6/5995 (0.10%)  6
Chest pain † 1  21/5992 (0.35%)  22 16/5995 (0.27%)  16
Complication associated with device † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cyst † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  2
Death † 1  12/5992 (0.20%)  12 16/5995 (0.27%)  16
Drug withdrawal syndrome † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Exercise tolerance decreased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Fatigue † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Gait disturbance † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Gastrointestinal complication associated with device † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Generalised oedema † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hernia pain † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hypothermia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Impaired healing † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Implant site erosion † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Incarcerated hernia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Infusion site extravasation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Localised oedema † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Malaise † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Medical device site haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Multiple organ dysfunction syndrome † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Non-cardiac chest pain † 1  132/5992 (2.20%)  153 133/5995 (2.22%)  164
Oedema peripheral † 1  4/5992 (0.07%)  4 4/5995 (0.07%)  4
Pain † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Peripheral swelling † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Pyrexia † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Stent-graft endoleak † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Sudden cardiac death † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Sudden death † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Systemic inflammatory response syndrome † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Vascular stent occlusion † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Vascular stent restenosis † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  5
Vascular stent thrombosis † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Hepatobiliary disorders     
Autoimmune hepatitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Bile duct obstruction † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Bile duct stone † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Biliary colic † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Biliary dyskinesia † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Cholangitis † 1  3/5992 (0.05%)  3 3/5995 (0.05%)  3
Cholecystitis † 1  14/5992 (0.23%)  14 10/5995 (0.17%)  10
Cholecystitis acute † 1  14/5992 (0.23%)  14 12/5995 (0.20%)  12
Cholecystitis chronic † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Cholelithiasis † 1  24/5992 (0.40%)  25 14/5995 (0.23%)  14
Cholelithiasis obstructive † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Chronic hepatic failure † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cirrhosis alcoholic † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cryptogenic cirrhosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Drug-induced liver injury † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hepatic cirrhosis † 1  2/5992 (0.03%)  2 4/5995 (0.07%)  4
Hepatic cyst † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Hepatic function abnormal † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hepatic mass † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hepatic steatosis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hepatic vascular thrombosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Liver disorder † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Liver injury † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Non-alcoholic fatty liver † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Portal vein thrombosis † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Immune system disorders     
Anaphylactic reaction † 1  4/5992 (0.07%)  4 1/5995 (0.02%)  1
Anaphylactic shock † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Drug hypersensitivity † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Hypersensitivity † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Infections and infestations     
Abdominal abscess † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Abdominal wall abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Abscess limb † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Abscess neck † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Abscess of salivary gland † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Acute sinusitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Anal abscess † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Appendicitis † 1  9/5992 (0.15%)  9 9/5995 (0.15%)  9
Appendicitis perforated † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Arthritis bacterial † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Arthritis infective † 1  2/5992 (0.03%)  3 1/5995 (0.02%)  1
Bacteraemia † 1  6/5992 (0.10%)  6 3/5995 (0.05%)  3
Bacterial infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Bacterial sepsis † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Bone abscess † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Bronchiolitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Bronchitis † 1  26/5992 (0.43%)  26 18/5995 (0.30%)  19
Bronchitis viral † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Campylobacter infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Campylobacter sepsis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Catheter site infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cellulitis † 1  71/5992 (1.18%)  81 48/5995 (0.80%)  52
Cellulitis pasteurella † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Cellulitis staphylococcal † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Cellulitis streptococcal † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  2
Cholecystitis infective † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Chronic sinusitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Chronic tonsillitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Clostridium difficile colitis † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  3
Clostridium difficile infection † 1  2/5992 (0.03%)  2 4/5995 (0.07%)  4
Colonic abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Cystitis † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Dengue fever † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Device related infection † 1  7/5992 (0.12%)  8 4/5995 (0.07%)  4
Device related sepsis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Diabetic foot infection † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Diabetic gangrene † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Diarrhoea infectious † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Diverticulitis † 1  17/5992 (0.28%)  22 23/5995 (0.38%)  26
Emphysematous cystitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Empyema † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Encephalitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Endocarditis † 1  1/5992 (0.02%)  1 4/5995 (0.07%)  4
Enterococcal bacteraemia † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Epididymitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Escherichia bacteraemia † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Escherichia infection † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Escherichia sepsis † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Escherichia urinary tract infection † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Extradural abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Gangrene † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Gastroenteritis † 1  13/5992 (0.22%)  13 10/5995 (0.17%)  10
Gastroenteritis bacterial † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastroenteritis viral † 1  3/5992 (0.05%)  3 7/5995 (0.12%)  7
Groin abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Groin infection † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
H1N1 influenza † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Hepatitis A † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hepatitis B † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Herpes zoster † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Human anaplasmosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Human ehrlichiosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Implant site infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Incision site abscess † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Incision site infection † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Infected skin ulcer † 1  3/5992 (0.05%)  4 0/5995 (0.00%)  0
Infectious colitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Infectious pleural effusion † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease † 1  2/5992 (0.03%)  3 3/5995 (0.05%)  4
Infective tenosynovitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Influenza † 1  10/5992 (0.17%)  10 12/5995 (0.20%)  12
Kidney infection † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Klebsiella bacteraemia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Labyrinthitis † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Laryngitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Localised infection † 1  5/5992 (0.08%)  6 3/5995 (0.05%)  3
Lower respiratory tract infection † 1  3/5992 (0.05%)  3 4/5995 (0.07%)  4
Lower respiratory tract infection viral † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Lyme disease † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Lymphangitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Mastoiditis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Necrotising fasciitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Neutropenic sepsis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Oesophageal candidiasis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Orchitis † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Osteomyelitis † 1  13/5992 (0.22%)  14 11/5995 (0.18%)  12
Osteomyelitis acute † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Parainfluenzae virus infection † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Paraspinal abscess † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Pelvic abscess † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Perirectal abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Peritonitis bacterial † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Pharyngeal abscess † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pharyngitis † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Pneumonia † 1  86/5992 (1.44%)  90 92/5995 (1.53%)  105
Pneumonia bacterial † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Pneumonia legionella † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pneumonia mycoplasmal † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Pneumonia pneumococcal † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Pneumonia staphylococcal † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Pneumonia streptococcal † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Pneumonia viral † 1  4/5992 (0.07%)  4 0/5995 (0.00%)  0
Post procedural cellulitis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Post procedural infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Postoperative abscess † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Postoperative wound infection † 1  1/5992 (0.02%)  1 5/5995 (0.08%)  5
Pulmonary sepsis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pyelonephritis † 1  4/5992 (0.07%)  4 6/5995 (0.10%)  6
Pyelonephritis acute † 1  4/5992 (0.07%)  4 1/5995 (0.02%)  1
Respiratory moniliasis † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Respiratory syncytial virus infection † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Respiratory tract infection † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Respiratory tract infection viral † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Rocky mountain spotted fever † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Rotavirus infection † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Scrotal abscess † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Sepsis † 1  27/5992 (0.45%)  27 37/5995 (0.62%)  39
Sepsis syndrome † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Septic arthritis staphylococcal † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Septic embolus † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Septic shock † 1  5/5992 (0.08%)  5 7/5995 (0.12%)  7
Sialoadenitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Sinusitis † 1  3/5992 (0.05%)  3 3/5995 (0.05%)  3
Staphylococcal bacteraemia † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Staphylococcal infection † 1  3/5992 (0.05%)  3 6/5995 (0.10%)  6
Staphylococcal osteomyelitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Staphylococcal sepsis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Staphylococcal skin infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Streptococcal bacteraemia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Streptococcal infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Subcutaneous abscess † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Tonsillitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Tooth abscess † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Tooth infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Tracheobronchitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Upper respiratory tract infection † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Urinary tract infection † 1  40/5992 (0.67%)  41 30/5995 (0.50%)  30
Urinary tract infection bacterial † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Urinary tract infection enterococcal † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Urosepsis † 1  7/5992 (0.12%)  7 13/5995 (0.22%)  13
Vascular stent infection † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Vestibular neuronitis † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Viral infection † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Viral upper respiratory tract infection † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Vulvitis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
West Nile viral infection † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Wound abscess † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Wound infection † 1  4/5992 (0.07%)  4 1/5995 (0.02%)  1
Wound infection pseudomonas † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Wound infection staphylococcal † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Injury, poisoning and procedural complications     
Abdominal injury † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Accidental overdose † 1  1/5992 (0.02%)  1 3/5995 (0.05%)  3
Alcohol poisoning † 1  2/5992 (0.03%)  2 4/5995 (0.07%)  5
Anaemia postoperative † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Anastomotic ulcer haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Animal bite † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Ankle fracture † 1  4/5992 (0.07%)  4 6/5995 (0.10%)  6
Arterial bypass thrombosis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Arterial injury † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Bladder injury † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Brain contusion † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Cardiac contusion † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Cardiac valve replacement complication † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Cartilage injury † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cervical vertebral fracture † 1  2/5992 (0.03%)  2 5/5995 (0.08%)  5
Chest injury † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Clavicle fracture † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Concussion † 1  1/5992 (0.02%)  1 4/5995 (0.07%)  4
Contusion † 1  3/5992 (0.05%)  3 3/5995 (0.05%)  3
Craniocerebral injury † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Cystitis radiation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Delayed recovery from anaesthesia † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Extradural haematoma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Facial bones fracture † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Fall † 1  15/5992 (0.25%)  17 21/5995 (0.35%)  21
Femoral neck fracture † 1  4/5992 (0.07%)  4 2/5995 (0.03%)  2
Femur fracture † 1  2/5992 (0.03%)  2 10/5995 (0.17%)  11
Fibula fracture † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Foot fracture † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Forearm fracture † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Fractured sacrum † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Gastrointestinal stoma complication † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Hand fracture † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Head injury † 1  2/5992 (0.03%)  2 4/5995 (0.07%)  4
Hip fracture † 1  5/5992 (0.08%)  5 10/5995 (0.17%)  10
Humerus fracture † 1  6/5992 (0.10%)  6 6/5995 (0.10%)  6
Ilium fracture † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Incarcerated incisional hernia † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Incision site complication † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Incision site haemorrhage † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Incisional hernia † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Incomplete spinal fusion † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Intentional overdose † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Intestinal anastomosis complication † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Jaw fracture † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  2
Joint capsule rupture † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Joint dislocation † 1  3/5992 (0.05%)  4 4/5995 (0.07%)  4
Joint dislocation postoperative † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Joint injury † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Kidney contusion † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Laceration † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Ligament rupture † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Ligament sprain † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Limb injury † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Limb traumatic amputation † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Liver contusion † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Lower limb fracture † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Lumbar vertebral fracture † 1  1/5992 (0.02%)  1 4/5995 (0.07%)  4
Meniscus injury † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Mental status changes postoperative † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Multiple fractures † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Multiple injuries † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Muscle strain † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Patella fracture † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Pelvic fracture † 1  3/5992 (0.05%)  3 1/5995 (0.02%)  1
Periprosthetic fracture † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Pneumonitis chemical † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Pneumothorax traumatic † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Post laminectomy syndrome † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Post procedural bile leak † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Post procedural complication † 1  3/5992 (0.05%)  3 2/5995 (0.03%)  2
Post procedural discharge † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Post procedural haematoma † 1  2/5992 (0.03%)  2 6/5995 (0.10%)  7
Post procedural haematuria † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Post procedural haemorrhage † 1  3/5992 (0.05%)  3 1/5995 (0.02%)  1
Post procedural myocardial infarction † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Post procedural swelling † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Postoperative fever † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Postoperative ileus † 1  1/5992 (0.02%)  1 5/5995 (0.08%)  5
Postoperative renal failure † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Postoperative respiratory failure † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Postoperative thoracic procedure complication † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Postoperative wound complication † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Postpericardiotomy syndrome † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Procedural complication † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Procedural haemorrhage † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Procedural hypotension † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Procedural pain † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Procedural pneumothorax † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Pubis fracture † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Pulmonary contusion † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Radius fracture † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Rib fracture † 1  9/5992 (0.15%)  9 9/5995 (0.15%)  9
Road traffic accident † 1  9/5992 (0.15%)  9 5/5995 (0.08%)  5
Scapula fracture † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Seroma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Shunt malfunction † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Shunt occlusion † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Skin abrasion † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Skull fracture † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Spinal compression fracture † 1  0/5992 (0.00%)  0 2/5995 (0.03%)  2
Spinal fracture † 1  3/5992 (0.05%)  3 1/5995 (0.02%)  1
Splenic rupture † 1  1/5992 (0.02%)  1 3/5995 (0.05%)  3
Stab wound † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Subdural haematoma † 1  7/5992 (0.12%)  8 5/5995 (0.08%)  5
Tendon rupture † 1  1/5992 (0.02%)  1 3/5995 (0.05%)  3
Tibia fracture † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Traumatic arthritis † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Traumatic haematoma † 1  4/5992 (0.07%)  4 4/5995 (0.07%)  4
Traumatic haemorrhage † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Traumatic haemothorax † 1  3/5992 (0.05%)  3 0/5995 (0.00%)  0
Traumatic intracranial haemorrhage † 1  2/5992 (0.03%)  2 2/5995 (0.03%)  2
Upper limb fracture † 1  4/5992 (0.07%)  4 1/5995 (0.02%)  1
Urinary retention postoperative † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Vascular pseudoaneurysm † 1  2/5992 (0.03%)  2 3/5995 (0.05%)  3
Vascular pseudoaneurysm ruptured † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Weaning failure † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Wound † 1  1/5992 (0.02%)  2 0/5995 (0.00%)  0
Wound dehiscence † 1  1/5992 (0.02%)  1 2/5995 (0.03%)  2
Wound haematoma † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Wrist fracture † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Investigations     
Ammonia increased † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Aortic bruit † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Blood calcium decreased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Blood creatinine increased † 1  2/5992 (0.03%)  2 0/5995 (0.00%)  0
Blood glucose increased † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Blood immunoglobulin G decreased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Blood potassium increased † 1  1/5992 (0.02%)  1 1/5995 (0.02%)  1
Blood pressure increased † 1  2/5992 (0.03%)  2 1/5995 (0.02%)  1
Blood sodium increased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Blood urea increased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Blood urine present † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Body temperature increased † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
Cardiac stress test abnormal † 1  0/5992 (0.00%)  0 1/5995 (0.02%)  1
Coagulation test abnormal † 1  1/5992 (0.02%)  1 0/5995 (0.00%)  0
ECG signs of myocardial ischaemia † 1  1/5992 (0.02%)