MODIFY II: A Study of MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-002)
Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT01513239
Collaborator
(none)
1,203
3
39.6
Study Details
Study Description
Brief Summary
MK-3415A is the combination of monoclonal antibodies to Clostridium (C.) difficile toxin A (MK-3415) and toxin B (MK-6072). This study will investigate whether: 1) treatment with MK-6072 or MK-3415A in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium Difficile Infection (CDI) recurrence compared with placebo; and 2) MK-6072 and MK-3415A will be generally well tolerated in participants receiving SOC therapy for CDI compared with placebo.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
An extended 9-month follow-up to assess for CDI recurrence through Month 12 will be conducted in a subset of participants.
Study Design
Study Type:
Interventional
Actual Enrollment
:
1203 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY II)
Actual Study Start Date
:
Feb 1, 2012
Actual Primary Completion Date
:
May 22, 2015
Actual Study Completion Date
:
May 22, 2015
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: MK-6072 + SOC Single intravenous (IV) infusion of 10 mg/kg MK-6072 + Standard of Care (SOC) for CDI |
Biological: MK-6072
Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)
Drug: SOC
SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
|
| Experimental: MK-3415A + SOC Single IV infusion of 10 mg/kg MK-3415A + SOC for CDI |
Biological: MK-3415A
Single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)
Drug: SOC
SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
|
| Placebo Comparator: Placebo + SOC Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI |
Biological: Placebo
Single IV infusion of normal saline (0.9% sodium chloride)
Drug: SOC
SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With CDI Recurrence [12 weeks]
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.
- Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment [Up to 4 weeks]
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.
- Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment [Up to 4 weeks]
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.
- Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment [Up to 4 weeks]
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.
- Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment [Up to 4 weeks]
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.
- Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion [Up to 24 hours]
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.
Secondary Outcome Measures
- Percentage of Participants With Global Cure [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI [12 weeks]
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).
- Percentage of Participants With CDI Recurrence in Those 65 Years and Older [12 weeks]
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.
- Percentage of Participants With CDI Recurrence in Those With Compromised Immunity [12 weeks]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Participant has a diagnosis of CDI defined as: a) presence of diarrhea (passage of 3 or more loose stools in 24 or fewer hours); and b) positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion.
-
Participant is receiving SOC therapy (i.e., oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole) for CDI.
-
Participant is highly unlikely to become pregnant or to impregnate a partner by meeting at least one of the following criteria: a) females not of reproductive potential (i.e., one who has either (1) reached natural menopause, defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone [FSH] levels in the postmenopausal range, or 12 months of spontaneous amenorrhea not including cases with an underlying disease, such as anorexia nervosa, that causes amenorrhea; (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation); or b) participants of reproductive potential who agree to remain abstinent or use (or have their partner use) two acceptable methods of birth control (i.e., intrauterine device [IUD], diaphragm with spermicide; contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or progestational agent including oral, subcutaneous, intrauterine, or intramuscular agents) starting at enrollment and throughout the 12-week study.
Exclusion Criteria:
-
Participant with an uncontrolled chronic diarrheal illness such that their normal 24-hour bowel movement habit is 3 or more loose stools.
-
Participant with planned surgery for CDI within 24 hours.
-
Female participant with a positive pregnancy test in the 48 hours before infusion and pre-menopausal females who are not sterilized and therefore have the potential to bear a child who are unwilling to undergo pregnancy testing.
-
Female participant breast feeding or planning to breast feed before completion of the 12-week study.
-
Female participant planning to donate ova before completion of the 12-week study and male participants planning to impregnate or donate sperm before completion of the 12-week study.
-
Participant has previously participated in this study, has previously received MK-3415 or MK-6072 (either alone or in combination), has received a C. difficile vaccine, or has received another experimental monoclonal antibody against C. difficile toxin A or
-
Participant plans to donate blood and/or blood products within 6 months after infusion.
-
Participant has received immune globulin within 6 months before infusion or is planning to receive immune globulin before completion of the 12-week study.
-
Treatment with SOC therapy is planned for longer than 14 days.
-
Participant has received more than a 24-hour regimen of cholestyramine, colestimide, rifaximin, or nitazoxanide within 14 days before infusion or plans to receive these medication before completion of the 12-week study period.
-
Participant plans to take medications that are given to decrease gastrointestinal peristalsis, such as loperamide (Imodium™) or diphenoxylate hydrochloride/atropine sulfate (Lomotil™) any time during the 14 days after infusion. Participants receiving opioid medications at the onset of diarrhea may be included if they are on a stable dose or if there is anticipation of a dose decrease or cessation of use.
-
Participant plans to take the probiotic Saccaromyces boulardii or plans to receive fecal transplantation therapy, or any other therapies that have been demonstrated to decrease CDI recurrence at any time after infusion (Day 1) and through completion of the 12-week study period.
-
Participant has received another investigational study agent within the past 30 days or is currently participating in or scheduled to participate in any other clinical study with an investigational agent during the 12-week study.
-
Participant is not expected to survive for 72 hours.
-
Participant has any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant, would make it unlikely for the participant to complete the study, or would confound the results of the study.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT01513239
Other Study ID Numbers:
- 3415A-002
- 132231
- 2011-004994-94
First Posted:
Jan 20, 2012
Last Update Posted:
Sep 5, 2018
Last Verified:
Aug 1, 2018
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Merck Sharp & Dohme LLC
Additional relevant MeSH terms:
Study Results
Participant Flow
| 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 Detail |
| 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 |
|---|---|---|---|---|---|---|
| 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 | 407 | 399 | 0 | 0 | 0 |
| Treated | 391 | 396 | 381 | 0 | 0 | 0 |
| All Participants as Treated | 390 | 396 | 381 | 0 | 0 | 0 |
| COMPLETED | 322 | 337 | 311 | 0 | 0 | 0 |
| NOT COMPLETED | 75 | 70 | 88 | 0 | 0 | 0 |
| Period Title: Period 1: Main Phase | ||||||
| STARTED | 0 | 0 | 0 | 112 | 100 | 83 |
| COMPLETED | 0 | 0 | 0 | 102 | 90 | 78 |
| NOT COMPLETED | 0 | 0 | 0 | 10 | 10 | 5 |
Baseline Characteristics
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC | Total |
|---|---|---|---|---|
| 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 Participants | 397 | 407 | 399 | 1203 |
| Age (Years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Years] |
65.9
(17.3)
|
62.6
(17.5)
|
64.3
(16.4)
|
64.2
(17.1)
|
| Sex: Female, Male (Count of 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%
|
Outcome Measures
| Title | Percentage of Participants With CDI Recurrence |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 395 | 378 |
| Number [Percentage of participants] |
14.9
3.8%
|
15.7
3.9%
|
25.7
6.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -10.7 | |
| Confidence Interval |
(2-Sided) 95% -16.4 to -5.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -9.9 | |
| Confidence Interval |
(2-Sided) 95% -15.5 to -4.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, MK-6072 + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -0.8 | |
| Confidence Interval |
(2-Sided) 95% -5.9 to 4.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus MK-6072 + SOC | |
| Title | Percentage of Participants With Global Cure |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 395 | 378 |
| Number [Percentage of participants] |
57.4
14.5%
|
66.8
16.4%
|
52.1
13.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | 5.2 | |
| Confidence Interval |
(2-Sided) 95% -1.8 to 12.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | 14.6 | |
| Confidence Interval |
(2-Sided) 95% 7.7 to 21.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, MK-6072 + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -9.4 | |
| Confidence Interval |
(2-Sided) 95% -16.1 to -2.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus MK-6072 + SOC | |
| Title | Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 282 | 326 | 294 |
| Number [Percentage of participants] |
20.6
5.2%
|
19.0
4.7%
|
33.0
8.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -11.9 | |
| Confidence Interval |
(2-Sided) 95% -19.0 to -4.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | -13.7 | |
| Confidence Interval |
(2-Sided) 95% -20.4 to -6.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, MK-6072 + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| 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 | ||
| Method of Estimation | Estimation Parameter | Adjusted Difference |
| Estimated Value | 1.6 | |
| Confidence Interval |
(2-Sided) 95% -4.6 to 8.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus MK-6072 + SOC | |
| Title | Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 396 | 381 |
| Number [Percentage of participants] |
57.4
14.5%
|
58.1
14.3%
|
60.4
15.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.408 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -2.9 | |
| Confidence Interval |
(2-Sided) 95% -9.8 to 4.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo +SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.517 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -2.3 | |
| Confidence Interval |
(2-Sided) 95% -9.2 to 4.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
| Title | Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 396 | 381 |
| Number [Percentage of participants] |
6.7
1.7%
|
6.8
1.7%
|
6.8
1.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.931 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -0.2 | |
| Confidence Interval |
(2-Sided) 95% -3.8 to 3.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.997 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 3.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
| Title | Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 396 | 381 |
| Number [Percentage of participants] |
0.8
0.2%
|
0.0
0%
|
0.3
0.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.328 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 0.5 | |
| Confidence Interval |
(2-Sided) 95% -0.8 to 2.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.308 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -0.3 | |
| Confidence Interval |
(2-Sided) 95% -1.5 to 0.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
| Title | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 396 | 381 |
| Number [Percentage of participants] |
0
0%
|
0
0%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | >0.999 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -1.0 to 1.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | >0.999 |
| Comments | ||
| Method | Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -1.0 to 1.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
| Title | Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 390 | 396 | 381 |
| Number [Percentage of participants] |
7.2
1.8%
|
8.8
2.2%
|
7.6
1.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | MK-3415A + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -0.4 | |
| Confidence Interval |
(2-Sided) 95% -4.2 to 3.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-3415A + SOC minus Placebo + SOC | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | MK-6072 + SOC, Placebo + SOC |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 1.2 | |
| Confidence Interval |
(2-Sided) 95% -2.7 to 5.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MK-6072 + SOC minus Placebo + SOC | |
| Title | Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|
| 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 |
| Measure Participants | 104 | 113 | 110 |
| Number [Percentage of participants] |
20.2
5.1%
|
23.9
5.9%
|
42.7
10.7%
|
| Title | Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated participants with the 027 ribotype |
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC |
|---|---|---|---|
| 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 |
| Measure Participants | 39 | 43 | 64 |
| Number [Percentage of participants] |
12.8
3.2%
|
20.9
5.1%
|
32.8
8.2%
|
| Title | Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated participants with an epidemic strain |
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC |
|---|---|---|---|
| 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 |
| Measure Participants | 116 | 102 | 127 |
| Number [Percentage of participants] |
14.7
3.7%
|
18.6
4.6%
|
29.1
7.3%
|
| Title | Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated participants with clinically severe CDI |
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC |
|---|---|---|---|
| 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 |
| Measure Participants | 80 | 55 | 65 |
| Number [Percentage of participants] |
11.3
2.8%
|
10.9
2.7%
|
20.0
5%
|
| Title | Percentage of Participants With CDI Recurrence in Those 65 Years and Older |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated participants 65 years and older. |
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC |
|---|---|---|---|
| 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 |
| Measure Participants | 241 | 205 | 206 |
| Number [Percentage of participants] |
17.4
4.4%
|
15.6
3.8%
|
29.6
7.4%
|
| Title | Percentage of Participants With CDI Recurrence in Those With Compromised Immunity |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated participants with compromised immunity |
| Arm/Group Title | MK-3415A + SOC | MK-6072 + SOC | Placebo + SOC |
|---|---|---|---|
| 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 |
| Measure Participants | 85 | 91 | 61 |
| Number [Percentage of participants] |
16.5
4.2%
|
12.1
3%
|
26.2
6.6%
|
Adverse Events
| 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 | |||||||
| 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 (%) | # 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 | 31/390 (7.9%) | 25/396 (6.3%) | 33/381 (8.7%) | 1/1 (100%) | 2/112 (1.8%) | 5/100 (5%) | 2/83 (2.4%) | |||||||
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 (30.3%) | 111/396 (28%) | 129/381 (33.9%) | 1/1 (100%) | 6/112 (5.4%) | 7/100 (7%) | 3/83 (3.6%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Anaemia | 2/390 (0.5%) | 2 | 3/396 (0.8%) | 3 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Anaemia of malignant disease | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Coagulopathy | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Disseminated intravascular coagulation | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Febrile neutropenia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haemolytic anaemia | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haemorrhagic anaemia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Leukopenia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Neutropenia | 2/390 (0.5%) | 2 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Sickle cell anaemia with crisis | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac disorders | ||||||||||||||
| Acute coronary syndrome | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Acute myocardial infarction | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Angina unstable | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Arrhythmia | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Arteriosclerosis coronary artery | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Atrial fibrillation | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 3/381 (0.8%) | 3 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Atrial flutter | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bradycardia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac arrest | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 2 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac disorder | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac failure | 5/390 (1.3%) | 5 | 3/396 (0.8%) | 3 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac failure acute | 2/390 (0.5%) | 2 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac failure chronic | 0/390 (0%) | 0 | 3/396 (0.8%) | 3 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardiac failure congestive | 5/390 (1.3%) | 5 | 5/396 (1.3%) | 5 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cardio-respiratory arrest | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Myocardial infarction | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Prinzmetal angina | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Supraventricular tachycardia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Endocrine disorders | ||||||||||||||
| Hyperparathyroidism | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hyperthyroidism | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Eye disorders | ||||||||||||||
| Blindness unilateral | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||
| Abdominal pain | 2/390 (0.5%) | 5 | 4/396 (1%) | 4 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Anal fissure | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Anal fistula | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Colitis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Diarrhoea | 4/390 (1%) | 4 | 7/396 (1.8%) | 7 | 6/381 (1.6%) | 6 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Diverticulum intestinal haemorrhagic | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Duodenal ulcer | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Dysphagia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gastric haemorrhage | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gastrointestinal haemorrhage | 1/390 (0.3%) | 1 | 4/396 (1%) | 4 | 2/381 (0.5%) | 3 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Gastrointestinal inflammation | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haematochezia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haemorrhagic erosive gastritis | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haemorrhoids | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Ileus | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Impaired gastric emptying | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Intestinal haemorrhage | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Intestinal perforation | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Large intestinal haemorrhage | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Mesenteric artery thrombosis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Nausea | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Oesophageal ulcer | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pancreatitis acute | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Small intestinal obstruction | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Subileus | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Vomiting | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 3 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| General disorders | ||||||||||||||
| Asthenia | 3/390 (0.8%) | 3 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Chest pain | 2/390 (0.5%) | 2 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Death | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Device breakage | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Device malfunction | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Disuse syndrome | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Drug withdrawal syndrome | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Fatigue | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| General physical health deterioration | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Generalised oedema | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Impaired healing | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Influenza like illness | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Multi-organ failure | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Non-cardiac chest pain | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Oedema peripheral | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pelvic mass | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pyrexia | 2/390 (0.5%) | 2 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Suprapubic pain | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||
| Cholangitis | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cholangitis acute | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cholecystitis acute | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hepatic cirrhosis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hepatic failure | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Immune system disorders | ||||||||||||||
| Anaphylactic reaction | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Infections and infestations | ||||||||||||||
| Abdominal abscess | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Anal abscess | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Arthritis infective | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bacteraemia | 3/390 (0.8%) | 3 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bursitis infective staphylococcal | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cellulitis | 2/390 (0.5%) | 2 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Clostridium difficile infection | 13/390 (3.3%) | 13 | 14/396 (3.5%) | 15 | 28/381 (7.3%) | 34 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 1/83 (1.2%) | 1 |
| Cytomegalovirus viraemia | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Device related infection | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Diabetic foot infection | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Diverticulitis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Endocarditis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Erysipelas | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Fungaemia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gangrene | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gastroenteritis | 0/390 (0%) | 0 | 2/396 (0.5%) | 3 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| HIV infection | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Infective spondylitis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Influenza | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Kidney infection | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lower respiratory tract infection viral | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lung abscess | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Meningitis tuberculous | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Necrotising fasciitis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Osteomyelitis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pelvic abscess | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Periodontitis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Peritonitis bacterial | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pneumonia | 9/390 (2.3%) | 9 | 5/396 (1.3%) | 5 | 9/381 (2.4%) | 9 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 1/83 (1.2%) | 1 |
| Pseudomembranous colitis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pyelonephritis | 0/390 (0%) | 0 | 2/396 (0.5%) | 2 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pyelonephritis acute | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Rhinitis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Sepsis | 3/390 (0.8%) | 3 | 6/396 (1.5%) | 7 | 13/381 (3.4%) | 14 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Septic shock | 3/390 (0.8%) | 3 | 1/396 (0.3%) | 1 | 6/381 (1.6%) | 6 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Upper respiratory tract infection | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Urinary tract infection | 7/390 (1.8%) | 7 | 9/396 (2.3%) | 11 | 4/381 (1%) | 4 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Urosepsis | 4/390 (1%) | 4 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Viraemia | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Wound infection | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Emphysematous cholecystitis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||
| Arteriovenous fistula site haematoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Concussion | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Femur fracture | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Frostbite | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hip fracture | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Intentional overdose | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Post procedural inflammation | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Spinal compression fracture | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Toxicity to various agents | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Investigations | ||||||||||||||
| Alanine aminotransferase increased | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Aspartate aminotransferase increased | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Blood lactic acid increased | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Blood pressure decreased | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Escherichia test positive | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| International normalised ratio increased | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||
| Dehydration | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Diabetic ketoacidosis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Fluid overload | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypercreatininaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hyperkalaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypoglycaemia | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypokalaemia | 0/390 (0%) | 0 | 2/396 (0.5%) | 3 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hyponatraemia | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Shock hypoglycaemic | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Arthritis reactive | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Muscular weakness | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Musculoskeletal chest pain | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Soft tissue necrosis | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Osteoporotic fracture | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Acute myeloid leukaemia | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Acute myeloid leukaemia recurrent | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Adenocarcinoma | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Adenocarcinoma gastric | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Basal cell carcinoma | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bile duct cancer | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bone cancer | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bone cancer metastatic | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Breast cancer metastatic | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Colon cancer | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Gastrointestinal cancer metastatic | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Glioblastoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hepatocellular carcinoma | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hodgkin's disease | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Leiomyosarcoma | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lung adenocarcinoma | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lung neoplasm | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lymphocytic leukaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Malignant melanoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Medulloblastoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Metastatic renal cell carcinoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Metastatic squamous cell carcinoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Myeloid leukaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Oesophageal carcinoma | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pancreatic carcinoma | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Peripheral T-cell lymphoma unspecified | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Plasma cell myeloma | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Prostate cancer | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Renal cancer metastatic | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Squamous cell carcinoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Bladder cancer | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Chronic lymphocytic leukaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lymphoma | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pancreatic carcinoma metastatic | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Nervous system disorders | ||||||||||||||
| Altered state of consciousness | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Aphasia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cerebellar haemorrhage | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cerebral haemorrhage | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cerebral infarction | 2/390 (0.5%) | 2 | 2/396 (0.5%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cerebral ischaemia | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Cerebrovascular accident | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 1/83 (1.2%) | 1 |
| Dementia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Dizziness | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Epilepsy | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hemiparesis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypoxic-ischaemic encephalopathy | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Ischaemic stroke | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Loss of consciousness | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Metabolic encephalopathy | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Neuralgia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Presyncope | 2/390 (0.5%) | 2 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Seizure | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 2/381 (0.5%) | 3 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Senile dementia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Spinal cord compression | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Status epilepticus | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Syncope | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Transient ischaemic attack | 2/390 (0.5%) | 2 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Wernicke's encephalopathy | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Encephalopathy | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haemorrhage intracranial | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||
| Agitation | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Anxiety disorder | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Confusional state | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Mental status changes | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||
| Acute kidney injury | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 4/381 (1%) | 4 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Calculus ureteric | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Chronic kidney disease | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 2 | 4/381 (1%) | 4 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Dysuria | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Haematuria | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Nephritic syndrome | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Urinary retention | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||||||
| Prostatitis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Acute pulmonary oedema | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 2 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Acute respiratory failure | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 1/100 (1%) | 1 | 0/83 (0%) | 0 |
| Asthma | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Chronic obstructive pulmonary disease | 3/390 (0.8%) | 3 | 2/396 (0.5%) | 2 | 3/381 (0.8%) | 3 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypoxia | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Interstitial lung disease | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Laryngeal stenosis | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Lung disorder | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pneumonia aspiration | 3/390 (0.8%) | 3 | 5/396 (1.3%) | 5 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pneumothorax | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pulmonary embolism | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 3/381 (0.8%) | 3 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 2/100 (2%) | 2 | 0/83 (0%) | 0 |
| Pulmonary haemorrhage | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Pulmonary oedema | 1/390 (0.3%) | 1 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Respiratory arrest | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Respiratory depression | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Respiratory distress | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Respiratory failure | 4/390 (1%) | 4 | 3/396 (0.8%) | 4 | 2/381 (0.5%) | 2 | 0/1 (0%) | 0 | 1/112 (0.9%) | 1 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Upper respiratory tract inflammation | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Decubitus ulcer | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Dermatitis allergic | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Skin ulcer | 0/390 (0%) | 0 | 1/396 (0.3%) | 2 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Vascular disorders | ||||||||||||||
| Circulatory collapse | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Deep vein thrombosis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 2/381 (0.5%) | 3 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Dry gangrene | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypertension | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypertensive crisis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Hypotension | 2/390 (0.5%) | 3 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Orthostatic hypotension | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Peripheral arterial occlusive disease | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Peripheral ischaemia | 0/390 (0%) | 0 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Phlebitis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Shock | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Thrombophlebitis | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 0/381 (0%) | 0 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
Other (Not Including 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 | 37/390 (9.5%) | 44/396 (11.1%) | 37/381 (9.7%) | 1/1 (100%) | 0/112 (0%) | 0/100 (0%) | 0/83 (0%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| Diarrhoea | 17/390 (4.4%) | 19 | 17/396 (4.3%) | 18 | 21/381 (5.5%) | 23 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Nausea | 17/390 (4.4%) | 17 | 23/396 (5.8%) | 23 | 12/381 (3.1%) | 12 | 0/1 (0%) | 0 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Infections and infestations | ||||||||||||||
| Clostridium difficile infection | 4/390 (1%) | 5 | 3/396 (0.8%) | 3 | 2/381 (0.5%) | 2 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Investigations | ||||||||||||||
| Lymphocyte count decreased | 1/390 (0.3%) | 1 | 0/396 (0%) | 0 | 1/381 (0.3%) | 1 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| Neutrophil count increased | 1/390 (0.3%) | 1 | 2/396 (0.5%) | 3 | 3/381 (0.8%) | 3 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
| White blood cell count increased | 0/390 (0%) | 0 | 1/396 (0.3%) | 1 | 1/381 (0.3%) | 1 | 1/1 (100%) | 1 | 0/112 (0%) | 0 | 0/100 (0%) | 0 | 0/83 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme Corp. |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT01513239
Other Study ID Numbers:
- 3415A-002
- 132231
- 2011-004994-94
First Posted:
Jan 20, 2012
Last Update Posted:
Sep 5, 2018
Last Verified:
Aug 1, 2018