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A Study of MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-002) (MODIFY II)

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ClinicalTrials.gov Identifier: NCT01513239
Recruitment Status : Completed
First Posted : January 20, 2012
Results First Posted : December 15, 2016
Last Update Posted : September 5, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Clostridium Difficile Infection
Interventions Biological: MK-6072
Biological: MK-3415A
Biological: Placebo
Drug: SOC
Enrollment 1203
Recruitment Details Male and female participants 18 years of age or older, diagnosed with Clostridium difficile infection (CDI) and receiving Standard of Care (SOC) therapy were recruited for this trial.
Pre-assignment Details  
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
Hide Arm/Group Description Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI 9 Month Extension (9-ME) for participants treated with a single IV infusion of 10 mg/kg MK-3415A + SOC 9-ME for participants treated with a single IV infusion of 10 mg/kg MK-6072 + SOC 9-ME for participants treated with Placebo
Period Title: Period 1: Main Phase
Started 397 [1] 407 [1] 399 [1] 0 0 0
Treated 391 [2] 396 [2] 381 [2] 0 0 0
All Participants as Treated 390 [3] 396 [4] 381 [4] 0 0 0
Completed 322 337 311 0 0 0
Not Completed 75 70 88 0 0 0
Reason Not Completed
Adverse Event             1             1             2             0             0             0
Death             29             22             32             0             0             0
Lost to Follow-up             11             10             6             0             0             0
Physician Decision             4             4             4             0             0             0
Protocol Violation             2             2             2             0             0             0
Technical Problems             1             2             0             0             0             0
Withdrawal by Subject             27             29             42             0             0             0
[1]
Randomized participants
[2]
Treated participants
[3]
One participant randomized to receive MK-3415A (MK-3415 plus MK-6072) received only MK-3415
[4]
Treatment actually received
Period Title: Period 2: 9 Month Extension Phase
Started 0 0 0 112 100 83
Completed 0 0 0 102 90 78
Not Completed 0 0 0 10 10 5
Reason Not Completed
Withdrawal by Subject             0             0             0             5             3             2
Death             0             0             0             2             5             2
Lost to Follow-up             0             0             0             2             1             0
Physician Decision             0             0             0             1             0             0
Technical Problems             0             0             0             0             1             1
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC Total
Hide Arm/Group Description Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI Total of all reporting groups
Overall Number of Baseline Participants 397 407 399 1203
Hide Baseline Analysis Population Description
All Randomized Participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 397 participants 407 participants 399 participants 1203 participants
65.9  (17.3) 62.6  (17.5) 64.3  (16.4) 64.2  (17.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 397 participants 407 participants 399 participants 1203 participants
Female
216
  54.4%
220
  54.1%
239
  59.9%
675
  56.1%
Male
181
  45.6%
187
  45.9%
160
  40.1%
528
  43.9%
1.Primary Outcome
Title Percentage of Participants With CDI Recurrence
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile after clinical cure of the initial CDI episode. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The (Full Analysis Set) FAS population consisting of all randomized participants with participants excluded for the failure to receive infusion of study medication; for lack of a positive local stool test for toxigenic C. difficile; or for failure to receive protocol defined standard of care therapy within a 1 day window of the infusion.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 395 378
Measure Type: Number
Unit of Measure: Percentage of participants
14.9 15.7 25.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -10.7
Confidence Interval (2-Sided) 95%
-16.4 to -5.1
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -9.9
Confidence Interval (2-Sided) 95%
-15.5 to -4.3
Estimation Comments MK-6072 + SOC minus Placebo + SOC
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, MK-6072 + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3718
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -0.8
Confidence Interval (2-Sided) 95%
-5.9 to 4.2
Estimation Comments MK-3415A + SOC minus MK-6072 + SOC
2.Primary Outcome
Title Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment
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 medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Time Frame Up to 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All Participants as Treated (APaT), based on the treatment actually received. One participant randomized to the MK- 3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 396 381
Measure Type: Number
Unit of Measure: Percentage of participants
57.4 58.1 60.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.408
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -2.9
Confidence Interval (2-Sided) 95%
-9.8 to 4.0
Estimation Comments MK-3415A + SOC minus Placebo +SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.517
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-9.2 to 4.6
Estimation Comments MK-6072 + SOC minus Placebo + SOC
3.Primary Outcome
Title Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
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 medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. A drug-related adverse event is determined by the investigator to be related to the drug.
Time Frame Up to 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
APaT based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 396 381
Measure Type: Number
Unit of Measure: Percentage of participants
6.7 6.8 6.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.931
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-3.8 to 3.5
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.997
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-3.7 to 3.6
Estimation Comments MK-6072 + SOC minus Placebo + SOC
4.Primary Outcome
Title Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
Hide Description A serious adverse event (SAE) is any AE occurring at any dose or during any use of the medicinal product that results in death; or is life threatening; or results in a persistent or significant disability/incapacity; or results in or prolongs an existing inpatient hospitalization; or is a congenital anomaly/birth defect; or other important medical events. A serious drug-related adverse event is determined by the investigator to be related to the drug.
Time Frame Up to 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
APaT based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 396 381
Measure Type: Number
Unit of Measure: Percentage of participants
0.8 0.0 0.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.328
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-0.8 to 2.0
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.308
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-1.5 to 0.7
Estimation Comments MK-6072 + SOC minus Placebo + SOC
5.Primary Outcome
Title Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment
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 medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Time Frame Up to 4 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
APaT based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 396 381
Measure Type: Number
Unit of Measure: Percentage of participants
0 0 0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-1.0 to 1.0
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-1.0 to 1.0
Estimation Comments MK-6072 + SOC minus Placebo + SOC
6.Primary Outcome
Title Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion
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 medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Time Frame Up to 24 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
APaT based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 396 381
Measure Type: Number
Unit of Measure: Percentage of participants
7.2 8.8 7.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-4.2 to 3.3
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Percentages
Estimated Value 1.2
Confidence Interval (2-Sided) 95%
-2.7 to 5.2
Estimation Comments MK-6072 + SOC minus Placebo + SOC
7.Secondary Outcome
Title Percentage of Participants With Global Cure
Hide Description Global cure is defined as the clinical cure of the initial CDI episode with no CDI recurrence through Week 12. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The FAS population consisting of all randomized participants with participants excluded for the failure to receive infusion of study medication; for lack of a positive local stool test for toxigenic C. difficile; or for failure to receive protocol defined standard of care therapy within a 1 day window of the infusion.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 390 395 378
Measure Type: Number
Unit of Measure: Percentage of participants
57.4 66.8 52.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0722
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value 5.2
Confidence Interval (2-Sided) 95%
-1.8 to 12.2
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value 14.6
Confidence Interval (2-Sided) 95%
7.7 to 21.4
Estimation Comments MK-6072 + SOC minus Placebo + SOC
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, MK-6072 + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9969
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -9.4
Confidence Interval (2-Sided) 95%
-16.1 to -2.7
Estimation Comments MK-3415A + SOC minus MK-6072 + SOC
8.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated participants who achieved a clinical cure of the initial CDI episode.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 282 326 294
Measure Type: Number
Unit of Measure: Percentage of participants
20.6 19.0 33.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -11.9
Confidence Interval (2-Sided) 95%
-19.0 to -4.7
Estimation Comments MK-3415A + SOC minus Placebo + SOC
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MK-6072 + SOC, Placebo + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value -13.7
Confidence Interval (2-Sided) 95%
-20.4 to -6.9
Estimation Comments MK-6072 + SOC minus Placebo + SOC
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MK-3415A + SOC, MK-6072 + SOC
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6962
Comments One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Difference
Estimated Value 1.6
Confidence Interval (2-Sided) 95%
-4.6 to 8.0
Estimation Comments MK-3415A + SOC minus MK-6072 + SOC
9.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated participants with a history of CDI in the past 6 months.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 104 113 110
Measure Type: Number
Unit of Measure: Percentage of participants
20.2 23.9 42.7
10.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The 027 ribotype is a more virulent, epidemic strain responsible for several outbreaks of disease associated with an increased risk of severity and mortality.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated participants with the 027 ribotype
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 39 43 64
Measure Type: Number
Unit of Measure: Percentage of participants
12.8 20.9 32.8
11.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. An epidemic strain includes ribotypes 027, 014, 002, 001, 106 or 020.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated participants with an epidemic strain
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 116 102 127
Measure Type: Number
Unit of Measure: Percentage of participants
14.7 18.6 29.1
12.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Participants with clinically severe CDI have a Zar Score greater than or equal to 2 points based on the presence of 1 or more of the following: 1) age >60 years old (1 point); 2) body temperature >38.3°C (>100°F) (1 point); 3) albumin level ˂2.5 mg/dl (1 point); 4) peripheral white blood cell count >15,000 cells/mm^3 within 48 hours (1 point); 5) endoscopic evidence of pseudomembranous colitis (2 points); and 6) treatment in Intensive Care Unit (2 points).
Time Frame 12 weeks
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Hide Analysis Population Description
Treated participants with clinically severe CDI
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 80 55 65
Measure Type: Number
Unit of Measure: Percentage of participants
11.3 10.9 20.0
13.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those 65 Years and Older
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Time Frame 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Treated participants 65 years and older.
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 241 205 206
Measure Type: Number
Unit of Measure: Percentage of participants
17.4 15.6 29.6
14.Secondary Outcome
Title Percentage of Participants With CDI Recurrence in Those With Compromised Immunity
Hide Description CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Compromised immunity is an active hematological malignancy (including leukemia, lymphoma, multiple myeloma), an active malignancy requiring recent cytotoxic chemotherapy, receipt of a prior hematopoietic stem cell transplant, receipt of a prior solid organ transplant, asplenia, or neutropenia/pancytopenia due to other conditions.
Time Frame 12 weeks
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Hide Analysis Population Description
Treated participants with compromised immunity
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC
Hide Arm/Group Description:
Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI
Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
Overall Number of Participants Analyzed 85 91 61
Measure Type: Number
Unit of Measure: Percentage of participants
16.5 12.1 26.2
Time Frame Non-serious adverse events up to Day 28; serious adverse events up to Day 90
Adverse Event Reporting Description

Main Phase AEs were assessed Systematically: All Participants as Treated (APaT), based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm was treated with MK-3415, but was not treated with MK-6072, is placed in his own arm for MK-3415 (not a randomized arm for this study).

9-Month Extension AEs were not planned for collection; and were therefore assessed Non-systematically.

 
Arm/Group Title MK-3415A + SOC MK-6072 + SOC Placebo + SOC MK-3415 + SOC MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
Hide Arm/Group Description Single IV infusion of 10 mg/kg MK 3415A + SOC for CDI Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI Single IV infusion of 10 mg/kg MK-3415 + SOC for CDI 9 Month Extension (9-ME) for participants treated with a single IV infusion of 10 mg/kg MK-3415A + SOC 9-ME for participants treated with a single IV infusion of 10 mg/kg MK-6072 + SOC 9-ME for participants treated with Placebo
All-Cause Mortality
MK-3415A + SOC MK-6072 + SOC Placebo + SOC MK-3415 + SOC MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   31/390 (7.95%)      25/396 (6.31%)      33/381 (8.66%)      1/1 (100.00%)      2/112 (1.79%)      5/100 (5.00%)      2/83 (2.41%)    
Show Serious Adverse Events Hide Serious Adverse Events
MK-3415A + SOC MK-6072 + SOC Placebo + SOC MK-3415 + SOC MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   118/390 (30.26%)      111/396 (28.03%)      129/381 (33.86%)      1/1 (100.00%)      6/112 (5.36%)      7/100 (7.00%)      3/83 (3.61%)    
Blood and lymphatic system disorders               
Anaemia  1  2/390 (0.51%)  2 3/396 (0.76%)  3 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Anaemia of malignant disease  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Coagulopathy  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Disseminated intravascular coagulation  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Febrile neutropenia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haemolytic anaemia  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haemorrhagic anaemia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Leukopenia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Neutropenia  1  2/390 (0.51%)  2 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Sickle cell anaemia with crisis  1  0/390 (0.00%)  0 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac disorders               
Acute coronary syndrome  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Acute myocardial infarction  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Angina unstable  1  0/390 (0.00%)  0 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Arrhythmia  1  1/390 (0.26%)  1 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Arteriosclerosis coronary artery  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Atrial fibrillation  1  1/390 (0.26%)  1 0/396 (0.00%)  0 3/381 (0.79%)  3 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Atrial flutter  1  0/390 (0.00%)  0 2/396 (0.51%)  2 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bradycardia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac arrest  1  1/390 (0.26%)  1 2/396 (0.51%)  2 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac disorder  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac failure  1  5/390 (1.28%)  5 3/396 (0.76%)  3 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac failure acute  1  2/390 (0.51%)  2 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac failure chronic  1  0/390 (0.00%)  0 3/396 (0.76%)  3 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardiac failure congestive  1  5/390 (1.28%)  5 5/396 (1.26%)  5 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cardio-respiratory arrest  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Myocardial infarction  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Prinzmetal angina  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Supraventricular tachycardia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Endocrine disorders               
Hyperparathyroidism  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hyperthyroidism  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Eye disorders               
Blindness unilateral  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gastrointestinal disorders               
Abdominal pain  1  2/390 (0.51%)  5 4/396 (1.01%)  4 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Anal fissure  1  0/390 (0.00%)  0 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Anal fistula  1  0/390 (0.00%)  0 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Colitis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Diarrhoea  1  4/390 (1.03%)  4 7/396 (1.77%)  7 6/381 (1.57%)  6 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Diverticulum intestinal haemorrhagic  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Duodenal ulcer  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Dysphagia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gastric haemorrhage  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gastrointestinal haemorrhage  1  1/390 (0.26%)  1 4/396 (1.01%)  4 2/381 (0.52%)  3 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Gastrointestinal inflammation  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haematochezia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haemorrhagic erosive gastritis  1  0/390 (0.00%)  0 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haemorrhoids  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Ileus  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Impaired gastric emptying  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Intestinal haemorrhage  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Intestinal perforation  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Large intestinal haemorrhage  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Mesenteric artery thrombosis  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Nausea  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Oesophageal ulcer  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pancreatitis acute  1  1/390 (0.26%)  1 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Small intestinal obstruction  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Subileus  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Vomiting  1  1/390 (0.26%)  1 2/396 (0.51%)  3 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
General disorders               
Asthenia  1  3/390 (0.77%)  3 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Chest pain  1  2/390 (0.51%)  2 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Death  1  1/390 (0.26%)  1 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Device breakage  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Device malfunction  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Disuse syndrome  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Drug withdrawal syndrome  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Fatigue  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
General physical health deterioration  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Generalised oedema  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Impaired healing  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Influenza like illness  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Multi-organ failure  1  0/390 (0.00%)  0 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Non-cardiac chest pain  1  1/390 (0.26%)  1 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Oedema peripheral  1  0/390 (0.00%)  0 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pelvic mass  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pyrexia  1  2/390 (0.51%)  2 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Suprapubic pain  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hepatobiliary disorders               
Cholangitis  1  1/390 (0.26%)  1 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cholangitis acute  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cholecystitis acute  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hepatic cirrhosis  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hepatic failure  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Immune system disorders               
Anaphylactic reaction  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Infections and infestations               
Abdominal abscess  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Anal abscess  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Arthritis infective  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bacteraemia  1  3/390 (0.77%)  3 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bursitis infective staphylococcal  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cellulitis  1  2/390 (0.51%)  2 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Clostridium difficile infection  1  13/390 (3.33%)  13 14/396 (3.54%)  15 28/381 (7.35%)  34 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 1/83 (1.20%)  1
Cytomegalovirus viraemia  1  0/390 (0.00%)  0 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Device related infection  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Diabetic foot infection  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Diverticulitis  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Endocarditis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Erysipelas  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Fungaemia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gangrene  1  0/390 (0.00%)  0 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gastroenteritis  1  0/390 (0.00%)  0 2/396 (0.51%)  3 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
HIV infection  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Infective spondylitis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Influenza  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Kidney infection  1  0/390 (0.00%)  0 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Lower respiratory tract infection viral  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Lung abscess  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Meningitis tuberculous  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Necrotising fasciitis  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Osteomyelitis  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pelvic abscess  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Periodontitis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Peritonitis bacterial  1  0/390 (0.00%)  0 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Pneumonia  1  9/390 (2.31%)  9 5/396 (1.26%)  5 9/381 (2.36%)  9 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 1/83 (1.20%)  1
Pseudomembranous colitis  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pyelonephritis  1  0/390 (0.00%)  0 2/396 (0.51%)  2 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pyelonephritis acute  1  1/390 (0.26%)  1 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Rhinitis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Sepsis  1  3/390 (0.77%)  3 6/396 (1.52%)  7 13/381 (3.41%)  14 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Septic shock  1  3/390 (0.77%)  3 1/396 (0.25%)  1 6/381 (1.57%)  6 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Upper respiratory tract infection  1  1/390 (0.26%)  1 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Urinary tract infection  1  7/390 (1.79%)  7 9/396 (2.27%)  11 4/381 (1.05%)  4 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Urosepsis  1  4/390 (1.03%)  4 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Viraemia  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Wound infection  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Emphysematous cholecystitis  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Injury, poisoning and procedural complications               
Arteriovenous fistula site haematoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Concussion  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Femur fracture  1  0/390 (0.00%)  0 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Frostbite  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hip fracture  1  0/390 (0.00%)  0 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Intentional overdose  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Post procedural inflammation  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Spinal compression fracture  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Toxicity to various agents  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Investigations               
Alanine aminotransferase increased  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Aspartate aminotransferase increased  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Blood lactic acid increased  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Blood pressure decreased  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Escherichia test positive  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
International normalised ratio increased  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Metabolism and nutrition disorders               
Dehydration  1  1/390 (0.26%)  1 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Diabetic ketoacidosis  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Fluid overload  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hypercreatininaemia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hyperkalaemia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 2/381 (0.52%)  2 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hypoglycaemia  1  1/390 (0.26%)  1 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hypokalaemia  1  0/390 (0.00%)  0 2/396 (0.51%)  3 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hyponatraemia  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Shock hypoglycaemic  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Musculoskeletal and connective tissue disorders               
Arthritis reactive  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Muscular weakness  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Musculoskeletal chest pain  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Soft tissue necrosis  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Osteoporotic fracture  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Acute myeloid leukaemia  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Acute myeloid leukaemia recurrent  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Adenocarcinoma  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Adenocarcinoma gastric  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Basal cell carcinoma  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bile duct cancer  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bone cancer  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bone cancer metastatic  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Breast cancer metastatic  1  0/390 (0.00%)  0 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Colon cancer  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Gastrointestinal cancer metastatic  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Glioblastoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hepatocellular carcinoma  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hodgkin's disease  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Leiomyosarcoma  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Lung adenocarcinoma  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Lung neoplasm  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Lymphocytic leukaemia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Malignant melanoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Medulloblastoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Metastatic renal cell carcinoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Metastatic squamous cell carcinoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Myeloid leukaemia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Oesophageal carcinoma  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Pancreatic carcinoma  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Peripheral T-cell lymphoma unspecified  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Plasma cell myeloma  1  0/390 (0.00%)  0 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Prostate cancer  1  1/390 (0.26%)  1 1/396 (0.25%)  1 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Renal cancer metastatic  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Squamous cell carcinoma  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Bladder cancer  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Chronic lymphocytic leukaemia  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Lymphoma  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Pancreatic carcinoma metastatic  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Nervous system disorders               
Altered state of consciousness  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Aphasia  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cerebellar haemorrhage  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cerebral haemorrhage  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cerebral infarction  1  2/390 (0.51%)  2 2/396 (0.51%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cerebral ischaemia  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Cerebrovascular accident  1  1/390 (0.26%)  1 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 1/83 (1.20%)  1
Dementia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Dizziness  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 1/112 (0.89%)  1 0/100 (0.00%)  0 0/83 (0.00%)  0
Epilepsy  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hemiparesis  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Hypoxic-ischaemic encephalopathy  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Ischaemic stroke  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Loss of consciousness  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Metabolic encephalopathy  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Neuralgia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Presyncope  1  2/390 (0.51%)  2 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Seizure  1  1/390 (0.26%)  1 0/396 (0.00%)  0 2/381 (0.52%)  3 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Senile dementia  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/0  0 0/0  0 0/0  0
Spinal cord compression  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Status epilepticus  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Syncope  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Transient ischaemic attack  1  2/390 (0.51%)  2 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Wernicke's encephalopathy  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Encephalopathy  1  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 1/1 (100.00%)  1 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haemorrhage intracranial  2  0/390 (0.00%)  0 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Psychiatric disorders               
Agitation  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Anxiety disorder  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Confusional state  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Mental status changes  1  1/390 (0.26%)  1 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Renal and urinary disorders               
Acute kidney injury  1  1/390 (0.26%)  1 1/396 (0.25%)  1 4/381 (1.05%)  4 1/1 (100.00%)  1 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Calculus ureteric  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Chronic kidney disease  1  1/390 (0.26%)  1 2/396 (0.51%)  2 4/381 (1.05%)  4 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Dysuria  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Haematuria  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Nephritic syndrome  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Urinary retention  1  0/390 (0.00%)  0 0/396 (0.00%)  0 1/381 (0.26%)  1 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Reproductive system and breast disorders               
Prostatitis  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Respiratory, thoracic and mediastinal disorders               
Acute pulmonary oedema  1  1/390 (0.26%)  1 1/396 (0.25%)  2 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 0/100 (0.00%)  0 0/83 (0.00%)  0
Acute respiratory failure  1  0/390 (0.00%)  0 1/396 (0.25%)  1 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0 1/100 (1.00%)  1 0/83 (0.00%)  0
Asthma  1  1/390 (0.26%)  1 0/396 (0.00%)  0 0/381 (0.00%)  0 0/1 (0.00%)  0 0/112 (0.00%)  0