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A Study to Evaluate the Safety and Efficacy of Inactivated Varicella-zoster Vaccine (VZV) as a Preventative Treatment for Herpes Zoster (HZ) and HZ-related Complications in Adult Participants With Solid Tumor or Hematologic Malignancy (V212-011)

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ClinicalTrials.gov Identifier: NCT01254630
Recruitment Status : Completed
First Posted : December 6, 2010
Results First Posted : April 13, 2018
Last Update Posted : October 31, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition Herpes Zoster
Interventions Biological: V212
Biological: Placebo
Enrollment 5305

Recruitment Details Adult participants with a diagnosis of solid tumor malignancy (STM) or hematologic malignancy (HM) were enrolled from 328 sites.
Pre-assignment Details Out of 5507 screened participants, 5305 were randomized. Twenty randomized participants were not included in analyses: 19 participants from a single site identified to have major Good Clinical Practice compliance issues and 1 participant that was not vaccinated. Thus, a total of 5285 were included in analyses.
Arm/Group Title V212-STM V212-HM Placebo-STM Placebo-HM
Hide Arm/Group Description Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Period Title: Overall Study
Started 1348 1288 1364 1285
Received Vaccination 1 1328 1277 1350 1275
Received Vaccination 2 1255 1217 1286 1226
Received Vaccination 3 1198 1178 1247 1194
Received Vaccination 4 1155 1145 1212 1160
Completed 546 0 552 0
Not Completed 802 1288 812 1285
Reason Not Completed
Adverse Event             36             15             40             8
Death             461             151             478             139
Lost to Follow-up             80             26             89             32
Physician Decision             24             8             16             7
Withdrawal by Subject             201             94             188             89
Study terminated by sponsor             0             994             0             1010
Status not recorded             0             0             1             0
Arm/Group Title V212-STM V212-HM Placebo-STM Placebo-HM Total
Hide Arm/Group Description Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart. Total of all reporting groups
Overall Number of Baseline Participants 1348 1288 1364 1285 5285
Hide Baseline Analysis Population Description
All randomized participants included in study analyses. Twenty randomized participants were not included in baseline analyses: 19 participants from a single site identified to have major Good Clinical Practice compliance issues and 1 participant that was not vaccinated.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1348 participants 1288 participants 1364 participants 1285 participants 5285 participants
57.6  (11.5) 61.0  (14.9) 57.7  (11.5) 61.4  (14.5) 59.4  (13.3)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1348 participants 1288 participants 1364 participants 1285 participants 5285 participants
Adults (between 18 and 64 years) 965 705 981 673 3324
From 65 to 84 years 379 558 378 589 1904
85 years and over 4 25 5 23 57
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1348 participants 1288 participants 1364 participants 1285 participants 5285 participants
<50 years 299 235 320 223 1077
≥50 years 1049 1053 1044 1062 4208
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1348 participants 1288 participants 1364 participants 1285 participants 5285 participants
Female
867
  64.3%
528
  41.0%
892
  65.4%
523
  40.7%
2810
  53.2%
Male
481
  35.7%
760
  59.0%
472
  34.6%
762
  59.3%
2475
  46.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1348 participants 1288 participants 1364 participants 1285 participants 5285 participants
American Indian or Alaska Native
17
   1.3%
2
   0.2%
14
   1.0%
2
   0.2%
35
   0.7%
Asian
55
   4.1%
110
   8.5%
64
   4.7%
94
   7.3%
323
   6.1%
Native Hawaiian or Other Pacific Islander
2
   0.1%
2
   0.2%
3
   0.2%
2
   0.2%
9
   0.2%
Black or African American
86
   6.4%
41
   3.2%
92
   6.7%
57
   4.4%
276
   5.2%
White
1044
  77.4%
976
  75.8%
1031
  75.6%
986
  76.7%
4037
  76.4%
More than one race
144
  10.7%
157
  12.2%
159
  11.7%
141
  11.0%
601
  11.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
   0.1%
3
   0.2%
4
   0.1%
1.Primary Outcome
Title Incidence of Confirmed Herpes-Zoster
Hide Description Clinical criteria for suspected HZ cases were the development of a papular or vesicular rash with a dermatomal or generalized distribution, or in the absence of a rash, clinical suspicion of VZV infection with or without the detection of VZV in diagnostic specimens from blood, cerebrospinal fluid, lung, liver, or other organ. All suspected cases of HZ were subjected to adjudication by the Clinical Adjudication Committee (CAC). Case confirmation was based on skin lesion polymerase chain reaction, if available, or by adjudication of the clinical case description by the CAC, conducted according to the CAC Standard Operations Procedure.
Time Frame Up to approximately 5 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This analysis was based on the Modified Intent-to-Treat (MITT) population. The MITT population for this outcome measure included all randomized participants in the STM population who received at least one dose of vaccination. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis.
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1328 1350
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Number of cases per 1000 person years
6.737
(4.222 to 10.200)
18.457
(14.118 to 23.709)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments Vaccine efficacy was calculated as 1 minus the hazard ratio of HZ in the V212 group versus the placebo group. The success criterion for vaccine efficacy required that the lower bound of the 97.5% Confidence Interval (CI) be >0.25.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 0.636
Confidence Interval (2-Sided) 97.5%
0.364 to 0.791
Estimation Comments Point estimate and 97.5% CI of vaccine efficacy (primary endpoint) were obtained from a Cox proportional hazards regression model, adjusting for age (<50 versus ≥50 years of age).
2.Primary Outcome
Title Percentage of Participants With One or More Serious Adverse Events
Hide Description An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in a persistent or significant disability or incapacity, results in or prolongs an existing hospitalization, is a congenital anomaly or birth defect, is a cancer, is an overdose, or is another important medical event.
Time Frame Up to 28 days after vaccination 4 (up to approximately 118 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants who received ≥1 dose of vaccination or placebo and had safety follow-up. Three participants in the STM population were cross-treated, these participants were excluded from the safety analyses. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1322 1346
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
22.5
(20.3 to 24.9)
21.0
(18.9 to 23.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
-1.8 to 4.5
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Incidence of Moderate to Severe Herpes-Zoster-Associated Pain
Hide Description Moderate to severe HZ-associated pain was defined as 2 or more occurrences of a score of 3 or greater (0-to-10 scale, where 0 is no pain and 10 is pain as bad as you can imagine) on the Zoster Brief Pain Inventory (ZBPI) at any time from HZ onset through the end of the 6 month HZ-follow-up period.
Time Frame Up to 6 months after onset of HZ (up to approximately 5 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This analysis was based on the MITT population. The MITT population for this outcome measure included all randomized participants in the STM population who received at least one dose of vaccination. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis.
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1328 1350
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Number of cases per 1000 person years
2.144
(0.862 to 4.417)
9.380
(6.373 to 13.314)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments Vaccine efficacy was calculated as 1 minus the hazard ratio of HZ in the V212 group versus the placebo group. The success criterion for vaccine efficacy required that the lower bound of the 95% CI be >0.25.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 0.771
Confidence Interval (2-Sided) 95%
0.480 to 0.899
Estimation Comments Point estimate and 95% CI of vaccine efficacy were obtained from a Cox proportional hazards regression model, adjusting for age (<50 versus ≥50 years of age).
4.Secondary Outcome
Title Incidence of Herpes-Zoster Complications
Hide Description The composite efficacy endpoint of the incidence of HZ complications was defined as the occurrence of any of the following during the study: hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, or administration of intravenous acyclovir therapy for treatment of HZ.
Time Frame Up to 6 months after onset of HZ (up to approximately 5 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This analysis was based on the MITT population. The MITT population for this outcome measure included all randomized participants in the STM population who received at least one dose of vaccination. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis.
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1328 1350
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Number of cases per 1000 person years
0.306
(0.008 to 1.706)
2.421
(1.045 to 4.770)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments Vaccine efficacy was calculated as 1 minus the hazard ratio of HZ in the V212 group versus the placebo group. The success criterion for vaccine efficacy required that the lower bound of the 95% CI be >0.25.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 0.874
Confidence Interval (2-Sided) 95%
-0.005 to 0.984
Estimation Comments Point estimate and 95% CI of vaccine efficacy were obtained from a Cox proportional hazards regression model, adjusting for age (<50 versus ≥50 years of age).
5.Secondary Outcome
Title Incidence of Postherpetic Neuralgia
Hide Description Postherpetic Neuralgia (PHN) was defined as pain in the area of the HZ rash with pain in the last 24 hours scored as 3 or greater (on a 0 to 10 scale, where 0 is no pain and 10 is pain as bad as you can imagine) on the ZBPI that persists or appears greater than or equal to 90 days after HZ rash onset.
Time Frame Up to 6 months after onset of HZ (up to approximately 5 years)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This analysis was based on the MITT population. The MITT population for this outcome measure included all randomized participants in the STM population who received at least one dose of vaccination. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis.
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1328 1350
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Number of cases per 1000 person years
0.306
(0.008 to 1.706)
1.210
(0.330 to 3.099)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments Vaccine efficacy was calculated as 1 minus the hazard ratio of HZ in the V212 group versus the placebo group. The success criterion for vaccine efficacy required that the lower bound of the 95% CI be >0.25.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 0.746
Confidence Interval (2-Sided) 95%
-1.275 to 0.972
Estimation Comments Point estimate and 95% CI of vaccine efficacy were obtained from a Cox proportional hazards regression model, adjusting for age (<50 versus ≥50 years of age).
6.Other Pre-specified Outcome
Title Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event
Hide Description An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. A serious adverse event (SAE) is an AE that results in death, is life threatening, results in a persistent or significant disability or incapacity, results in or prolongs an existing hospitalization, is a congenital anomaly or birth defect, is a cancer, is an overdose, or is another important medical event.
Time Frame Up to 28 days after vaccination 4 (up to approximately 118 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis population included all participants who received ≥1 dose of vaccination or placebo and had safety follow-up. Three participants in the STM population were cross-treated, these participants were excluded from the safety analyses. This endpoint was exploratory for the HM population, therefore that group was not included in this analysis
Arm/Group Title V212-STM Placebo-STM
Hide Arm/Group Description:
Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
Overall Number of Participants Analyzed 1322 1346
Measure Type: Number
Unit of Measure: percentage of participants
2.2 1.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection V212-STM, Placebo-STM
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-0.6 to 1.6
Estimation Comments [Not Specified]
Time Frame Adverse events were collected up to approximately 5 years after vaccination 1.
Adverse Event Reporting Description The All Subjects as Treated population included all participants who received ≥1 dose of vaccination or placebo and had safety follow-up. Three participants in the STM population were cross-treated, these participants were excluded from the safety analyses.
 
Arm/Group Title V212-STM V212-HM Placebo-STM Placebo-HM
Hide Arm/Group Description Participants with STM receiving chemotherapy randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with STM receiving chemotherapy randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart. Participants with HM randomized to receive placebo to V212 vaccine given as a 4-dose regimen administered ~30 days apart.
All-Cause Mortality
V212-STM V212-HM Placebo-STM Placebo-HM
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   472/1322 (35.70%)      159/1274 (12.48%)      488/1346 (36.26%)      146/1274 (11.46%)    
Show Serious Adverse Events Hide Serious Adverse Events
V212-STM V212-HM Placebo-STM Placebo-HM
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   794/1322 (60.06%)      500/1274 (39.25%)      808/1346 (60.03%)      507/1274 (39.80%)    
Blood and lymphatic system disorders         
Anaemia  1  9/1322 (0.68%)  9 16/1274 (1.26%)  19 24/1346 (1.78%)  25 11/1274 (0.86%)  11
Anaemia of chronic disease  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Anaemia of malignant disease  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 2/1274 (0.16%)  3
Autoimmune haemolytic anaemia  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Bone marrow failure  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Coagulopathy  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Febrile neutropenia  1  21/1322 (1.59%)  23 44/1274 (3.45%)  64 35/1346 (2.60%)  37 35/1274 (2.75%)  43
Haematotoxicity  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Haemolysis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Haemolytic anaemia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Haemorrhagic anaemia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Hypoprothrombinaemia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Iron deficiency anaemia  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Leukocytosis  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Leukopenia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Lymph node pain  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Lymphadenitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Lymphadenopathy  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Neutropenia  1  4/1322 (0.30%)  4 4/1274 (0.31%)  4 5/1346 (0.37%)  5 2/1274 (0.16%)  2
Pancytopenia  1  7/1322 (0.53%)  8 5/1274 (0.39%)  5 9/1346 (0.67%)  12 5/1274 (0.39%)  5
Splenomegaly  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Thrombocytopenia  1  5/1322 (0.38%)  6 4/1274 (0.31%)  5 5/1346 (0.37%)  5 4/1274 (0.31%)  4
Cardiac disorders         
Acute coronary syndrome  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Acute myocardial infarction  1  2/1322 (0.15%)  2 6/1274 (0.47%)  6 6/1346 (0.45%)  6 5/1274 (0.39%)  5
Angina pectoris  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Angina unstable  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Aortic valve sclerosis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Aortic valve stenosis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Arrhythmia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Atrial fibrillation  1  7/1322 (0.53%)  8 9/1274 (0.71%)  12 11/1346 (0.82%)  11 15/1274 (1.18%)  15
Atrial flutter  1  0/1322 (0.00%)  0 3/1274 (0.24%)  3 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Atrioventricular block second degree  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cardiac arrest  1  8/1322 (0.61%)  8 4/1274 (0.31%)  4 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cardiac failure  1  6/1322 (0.45%)  6 3/1274 (0.24%)  3 4/1346 (0.30%)  4 3/1274 (0.24%)  3
Cardiac failure acute  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  2
Cardiac failure chronic  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Cardiac failure congestive  1  9/1322 (0.68%)  11 11/1274 (0.86%)  12 6/1346 (0.45%)  7 10/1274 (0.78%)  15
Cardiac tamponade  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  2 0/1274 (0.00%)  0
Cardiac valve disease  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Cardiac ventricular thrombosis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cardio-respiratory arrest  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Cardiomyopathy  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Cardiomyopathy acute  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cardiopulmonary failure  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Cardiorenal syndrome  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Congestive cardiomyopathy  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Coronary artery disease  1  3/1322 (0.23%)  3 3/1274 (0.24%)  3 2/1346 (0.15%)  2 1/1274 (0.08%)  2
Coronary artery insufficiency  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ischaemic cardiomyopathy  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Mitral valve incompetence  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Myocardial infarction  1  3/1322 (0.23%)  3 4/1274 (0.31%)  4 4/1346 (0.30%)  4 4/1274 (0.31%)  4
Myocardial ischaemia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Palpitations  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pericardial effusion  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Pericardial haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pericarditis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Pulseless electrical activity  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Sinus node dysfunction  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Sinus tachycardia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Stress cardiomyopathy  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Supraventricular tachycardia  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Tachycardia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Ventricular dyssynchrony  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ventricular extrasystoles  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ventricular fibrillation  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Ventricular tachycardia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Congenital, familial and genetic disorders         
Dysplastic naevus syndrome  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Tracheo-oesophageal fistula  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Ear and labyrinth disorders         
Inner ear disorder  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Neurosensory hypoacusis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Vertigo  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Vertigo positional  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Endocrine disorders         
Adrenal insufficiency  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Carcinoid syndrome  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Cushing's syndrome  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Goitre  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Hypercalcaemia of malignancy  1  1/1322 (0.08%)  1 2/1274 (0.16%)  2 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Hyperthyroidism  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Hypothyroidism  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Inappropriate antidiuretic hormone secretion  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Thyroid mass  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Eye disorders         
Blindness transient  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cataract  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cortical visual impairment  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Myopia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Necrotising retinitis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Retinal detachment  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ulcerative keratitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Gastrointestinal disorders         
Abdominal hernia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Abdominal hernia obstructive  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Abdominal pain  1  9/1322 (0.68%)  10 3/1274 (0.24%)  3 7/1346 (0.52%)  8 1/1274 (0.08%)  1
Abdominal pain lower  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Abdominal pain upper  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 4/1346 (0.30%)  4 0/1274 (0.00%)  0
Abdominal wall haematoma  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Anal fissure  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Anal fistula  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ascites  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  2 0/1274 (0.00%)  0
Colitis  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 3/1346 (0.22%)  3 2/1274 (0.16%)  2
Colitis ischaemic  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Constipation  1  7/1322 (0.53%)  8 1/1274 (0.08%)  1 8/1346 (0.59%)  8 1/1274 (0.08%)  1
Crohn's disease  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cyclic vomiting syndrome  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Diarrhoea  1  17/1322 (1.29%)  20 1/1274 (0.08%)  1 13/1346 (0.97%)  15 3/1274 (0.24%)  3
Diarrhoea haemorrhagic  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Diverticular perforation  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Diverticulum  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Diverticulum intestinal  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Duodenal obstruction  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Duodenal ulcer haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Duodenitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Dyspepsia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Dysphagia  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 5/1346 (0.37%)  5 1/1274 (0.08%)  1
Enteritis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Enterocutaneous fistula  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Eosinophilic colitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Erosive oesophagitis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Faecaloma  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Gastric ulcer haemorrhage  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastritis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Gastritis erosive  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Gastrointestinal disorder  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Gastrointestinal haemorrhage  1  7/1322 (0.53%)  8 6/1274 (0.47%)  6 13/1346 (0.97%)  13 5/1274 (0.39%)  5
Gastrointestinal hypomotility  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastrointestinal obstruction  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastrointestinal pain  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastrointestinal perforation  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Haematemesis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Haematochezia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Haemorrhoidal haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Haemorrhoids  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hiatus hernia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Ileus  1  2/1322 (0.15%)  3 0/1274 (0.00%)  0 4/1346 (0.30%)  5 0/1274 (0.00%)  0
Impaired gastric emptying  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Incarcerated inguinal hernia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Inguinal hernia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Inguinal hernia strangulated  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Intestinal fibrosis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Intestinal ischaemia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Intestinal obstruction  1  12/1322 (0.91%)  16 3/1274 (0.24%)  4 10/1346 (0.74%)  12 1/1274 (0.08%)  1
Intestinal perforation  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Intestinal prolapse  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Large intestinal obstruction  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Large intestine perforation  1  3/1322 (0.23%)  3 1/1274 (0.08%)  1 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Large intestine polyp  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Lower gastrointestinal haemorrhage  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 2/1346 (0.15%)  3 0/1274 (0.00%)  0
Mallory-Weiss syndrome  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Mouth ulceration  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Nausea  1  4/1322 (0.30%)  4 1/1274 (0.08%)  3 5/1346 (0.37%)  6 1/1274 (0.08%)  1
Neutropenic colitis  1  0/1322 (0.00%)  0 3/1274 (0.24%)  3 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Obstruction gastric  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Odynophagia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Oesophageal perforation  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Oesophageal rupture  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Oesophageal spasm  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Oesophageal ulcer haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Oesophageal varices haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Oesophagitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Pancreatic cyst  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pancreatic insufficiency  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pancreatic mass  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pancreatitis  1  4/1322 (0.30%)  5 1/1274 (0.08%)  1 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Pancreatitis acute  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 3/1346 (0.22%)  3 0/1274 (0.00%)  0
Pancreatitis chronic  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Proctalgia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Proctitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Rectal haemorrhage  1  0/1322 (0.00%)  0 3/1274 (0.24%)  3 3/1346 (0.22%)  3 0/1274 (0.00%)  0
Rectal ulcer  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Retroperitoneal haemorrhage  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Salivary gland calculus  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Small intestinal obstruction  1  21/1322 (1.59%)  43 4/1274 (0.31%)  4 12/1346 (0.89%)  17 5/1274 (0.39%)  7
Small intestinal perforation  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Stomatitis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 4/1346 (0.30%)  4 0/1274 (0.00%)  0
Subileus  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Umbilical hernia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Upper gastrointestinal haemorrhage  1  1/1322 (0.08%)  1 3/1274 (0.24%)  3 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Volvulus  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Vomiting  1  11/1322 (0.83%)  11 2/1274 (0.16%)  4 13/1346 (0.97%)  16 3/1274 (0.24%)  3
General disorders         
Adverse drug reaction  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Asthenia  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 4/1346 (0.30%)  4 0/1274 (0.00%)  0
Chest discomfort  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Chest pain  1  6/1322 (0.45%)  6 4/1274 (0.31%)  4 12/1346 (0.89%)  13 8/1274 (0.63%)  9
Chills  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Complication associated with device  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Death  1  31/1322 (2.34%)  31 13/1274 (1.02%)  13 17/1346 (1.26%)  17 7/1274 (0.55%)  7
Drug withdrawal syndrome  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Fatigue  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Gait disturbance  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
General physical health deterioration  1  5/1322 (0.38%)  5 1/1274 (0.08%)  1 3/1346 (0.22%)  3 0/1274 (0.00%)  0
Generalised oedema  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Granuloma  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Impaired healing  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Incarcerated hernia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Malaise  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Medical device pain  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Mucosal haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Mucosal inflammation  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Multiple organ dysfunction syndrome  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Nodule  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Non-cardiac chest pain  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Oedema peripheral  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Organ failure  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pain  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Polyserositis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pyrexia  1  11/1322 (0.83%)  11 5/1274 (0.39%)  5 15/1346 (1.11%)  15 13/1274 (1.02%)  14
Sudden death  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Systemic inflammatory response syndrome  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ulcer haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Vascular stent thrombosis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Visceral pain  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Hepatobiliary disorders         
Acute hepatic failure  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Bile duct obstruction  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Bile duct stone  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Biliary colic  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Biloma  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cholangitis  1  4/1322 (0.30%)  5 0/1274 (0.00%)  0 7/1346 (0.52%)  8 0/1274 (0.00%)  0
Cholangitis acute  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Cholecystitis  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Cholecystitis acute  1  3/1322 (0.23%)  3 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cholecystitis chronic  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cholelithiasis  1  1/1322 (0.08%)  1 2/1274 (0.16%)  2 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Cholestasis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Drug-induced liver injury  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Gallbladder disorder  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Haemobilia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hepatic cirrhosis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 3/1274 (0.24%)  3
Hepatic failure  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Hepatic function abnormal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hepatic haemorrhage  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Hepatitis cholestatic  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hepatorenal syndrome  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hepatotoxicity  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Hyperbilirubinaemia  1  1/1322 (0.08%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  2 0/1274 (0.00%)  0
Jaundice cholestatic  1  1/1322 (0.08%)  1 1/1274 (0.08%)  2 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Liver injury  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Portal vein thrombosis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Immune system disorders         
Anaphylactic reaction  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Drug hypersensitivity  1  4/1322 (0.30%)  4 1/1274 (0.08%)  1 2/1346 (0.15%)  2 2/1274 (0.16%)  2
Graft versus host disease  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 3/1274 (0.24%)  3
Hypersensitivity  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 3/1346 (0.22%)  3 0/1274 (0.00%)  0
Hypogammaglobulinaemia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Sarcoidosis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Infections and infestations         
Abdominal abscess  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Abdominal infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Abdominal sepsis  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Abdominal wall abscess  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Abscess jaw  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Abscess limb  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Abscess soft tissue  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Anal abscess  1  1/1322 (0.08%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Appendicitis  1  1/1322 (0.08%)  1 2/1274 (0.16%)  2 6/1346 (0.45%)  6 3/1274 (0.24%)  3
Appendicitis perforated  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Arthritis bacterial  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Arthritis infective  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Atypical pneumonia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Bacillus bacteraemia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Bacteraemia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 6/1346 (0.45%)  6 3/1274 (0.24%)  3
Bacterial sepsis  1  2/1322 (0.15%)  2 3/1274 (0.24%)  3 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Bacterial tracheitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Biliary sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Breast abscess  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Breast cellulitis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Bronchiolitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Bronchitis  1  2/1322 (0.15%)  2 10/1274 (0.78%)  10 6/1346 (0.45%)  6 6/1274 (0.47%)  6
Bronchopulmonary aspergillosis  1  0/1322 (0.00%)  0 3/1274 (0.24%)  3 0/1346 (0.00%)  0 4/1274 (0.31%)  4
Campylobacter gastroenteritis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Cellulitis  1  12/1322 (0.91%)  19 13/1274 (1.02%)  18 19/1346 (1.41%)  21 13/1274 (1.02%)  14
Cellulitis staphylococcal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Cerebral aspergillosis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Chronic sinusitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Citrobacter sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Clostridial infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Clostridial sepsis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Clostridium difficile colitis  1  9/1322 (0.68%)  9 2/1274 (0.16%)  2 5/1346 (0.37%)  6 2/1274 (0.16%)  2
Clostridium difficile infection  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 4/1346 (0.30%)  4 1/1274 (0.08%)  1
Cystitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Dengue fever  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Device related infection  1  7/1322 (0.53%)  7 4/1274 (0.31%)  5 10/1346 (0.74%)  10 2/1274 (0.16%)  2
Device related sepsis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Diarrhoea infectious  1  0/1322 (0.00%)  0 3/1274 (0.24%)  3 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Disseminated cryptococcosis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Diverticulitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 4/1346 (0.30%)  5 2/1274 (0.16%)  4
Empyema  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Encephalitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Endocarditis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Endophthalmitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Enteritis infectious  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Enterococcal sepsis  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Epididymitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Erysipelas  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  4 0/1274 (0.00%)  0
Escherichia bacteraemia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Escherichia infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Escherichia sepsis  1  4/1322 (0.30%)  4 2/1274 (0.16%)  2 2/1346 (0.15%)  2 4/1274 (0.31%)  4
Escherichia urinary tract infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Extradural abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Febrile infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  2
Fungaemia  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Fungal oesophagitis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastroenteritis  1  6/1322 (0.45%)  6 5/1274 (0.39%)  5 5/1346 (0.37%)  5 4/1274 (0.31%)  5
Gastroenteritis rotavirus  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Gastroenteritis salmonella  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Gastroenteritis viral  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Gastrointestinal infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Genital herpes  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Groin abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
H1N1 influenza  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Haematoma infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Haemophilus bacteraemia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Hepatitis B  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Hepatitis C  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Hepatosplenic candidiasis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Herpes virus infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Herpes zoster  1  1/1322 (0.08%)  1 4/1274 (0.31%)  4 1/1346 (0.07%)  1 4/1274 (0.31%)  4
Herpes zoster disseminated  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Herpes zoster oticus  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Implant site infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Infected bite  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Infected fistula  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Infected seroma  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Infectious colitis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Infectious pleural effusion  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Infective exacerbation of chronic obstructive airways disease  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Influenza  1  3/1322 (0.23%)  3 4/1274 (0.31%)  4 3/1346 (0.22%)  3 6/1274 (0.47%)  7
Intestinal fistula infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Joint abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Kidney infection  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Klebsiella bacteraemia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Klebsiella sepsis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Labyrinthitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Listeria sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Lower respiratory tract infection  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 3/1274 (0.24%)  4
Lower respiratory tract infection bacterial  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Lower respiratory tract infection fungal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Lung abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Lung infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Lung infection pseudomonal  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Mediastinitis  1  1/1322 (0.08%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Meningitis aseptic  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Meningitis cryptococcal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Meningoencephalitis herpetic  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Metapneumovirus infection  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Muscle abscess  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Nasopharyngitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Necrotising fasciitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 3/1346 (0.22%)  3 0/1274 (0.00%)  0
Neutropenic sepsis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Ophthalmic herpes zoster  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Orchitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Osteomyelitis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Otitis media  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Paraspinal abscess  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pelvic abscess  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 4/1346 (0.30%)  4 0/1274 (0.00%)  0
Pelvic inflammatory disease  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Periodontitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Periorbital cellulitis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Perirectal abscess  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Peritonitis  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Peritonitis bacterial  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Peritonsillar abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pharyngitis streptococcal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pilonidal cyst  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Pleurisy viral  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Pneumocystis jirovecii pneumonia  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pneumonia  1  49/1322 (3.71%)  57 72/1274 (5.65%)  83 49/1346 (3.64%)  53 66/1274 (5.18%)  87
Pneumonia bacterial  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Pneumonia cytomegaloviral  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pneumonia fungal  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pneumonia influenzal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pneumonia klebsiella  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Pneumonia moraxella  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Pneumonia mycoplasmal  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Pneumonia necrotising  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pneumonia pneumococcal  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  2
Pneumonia pseudomonal  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pneumonia streptococcal  1  1/1322 (0.08%)  1 2/1274 (0.16%)  2 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Post procedural cellulitis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Post procedural infection  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Post procedural sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Postoperative wound infection  1  3/1322 (0.23%)  3 0/1274 (0.00%)  0 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Progressive multifocal leukoencephalopathy  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Pseudomembranous colitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Pseudomonal bacteraemia  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Pseudomonal sepsis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Psoas abscess  1  1/1322 (0.08%)  1 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Pulmonary sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 4/1274 (0.31%)  4
Pyelonephritis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 2/1274 (0.16%)  2
Pyelonephritis acute  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Pyomyositis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Rectal abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Renal abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Respiratory moniliasis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Respiratory syncytial virus infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Respiratory tract infection  1  2/1322 (0.15%)  2 1/1274 (0.08%)  1 3/1346 (0.22%)  3 1/1274 (0.08%)  1
Respiratory tract infection bacterial  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Rhinovirus infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Scrotal infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Sepsis  1  28/1322 (2.12%)  32 17/1274 (1.33%)  18 21/1346 (1.56%)  23 21/1274 (1.65%)  22
Sepsis syndrome  1  2/1322 (0.15%)  2 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Septic shock  1  6/1322 (0.45%)  6 7/1274 (0.55%)  7 7/1346 (0.52%)  7 10/1274 (0.78%)  10
Serratia bacteraemia  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Serratia sepsis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Sinusitis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Skin infection  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Soft tissue infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Splenic abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Staphylococcal abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Staphylococcal bacteraemia  1  2/1322 (0.15%)  3 0/1274 (0.00%)  0 2/1346 (0.15%)  2 0/1274 (0.00%)  0
Staphylococcal infection  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 1/1346 (0.07%)  1 1/1274 (0.08%)  1
Staphylococcal sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 2/1274 (0.16%)  2
Staphylococcal skin infection  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Stenotrophomonas sepsis  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Subcutaneous abscess  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Tonsillitis bacterial  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Tooth abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Tuberculosis  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Upper respiratory tract infection  1  0/1322 (0.00%)  0 2/1274 (0.16%)  2 2/1346 (0.15%)  2 4/1274 (0.31%)  4
Urinary tract infection  1  19/1322 (1.44%)  20 11/1274 (0.86%)  11 24/1346 (1.78%)  24 11/1274 (0.86%)  11
Urinary tract infection bacterial  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Urinary tract infection fungal  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Urinary tract infection staphylococcal  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Urosepsis  1  3/1322 (0.23%)  3 2/1274 (0.16%)  5 6/1346 (0.45%)  6 4/1274 (0.31%)  5
Varicella  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Varicella zoster pneumonia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Viraemia  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Viral infection  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Viral upper respiratory tract infection  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Vulval abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
West Nile viral infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 2/1274 (0.16%)  2
Wound abscess  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Wound infection  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 2/1346 (0.15%)  2 1/1274 (0.08%)  1
Injury, poisoning and procedural complications         
Abdominal wound dehiscence  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 0/1346 (0.00%)  0 1/1274 (0.08%)  1
Accidental overdose  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Acetabulum fracture  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0
Anastomotic stenosis  1  1/1322 (0.08%)  1 0/1274 (0.00%)  0 0/1346 (0.00%)  0 0/1274 (0.00%)  0
Ankle fracture  1  0/1322 (0.00%)  0 1/1274 (0.08%)  1 4/1346 (0.30%)  4 1/1274 (0.08%)  1
Cervical vertebral fracture  1  0/1322 (0.00%)  0 0/1274 (0.00%)  0 1/1346 (0.07%)  1 0/1274 (0.00%)  0